6,11-4-Carbon bridged erythromycin derivatives

ABSTRACT

Novel 6, 11-4-carbon bridged erythromycin derivatives and pharmaceutically-acceptable compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically-acceptable carrier are described. Also described are methods for treating bacterial infections by administering to an animal a pharmaceutical composition containing a therapeutically effective amount of a compound of the invention and processes for the preparation of such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/205,357, filed Jul. 25, 2002 (Attorney Docket Number ENP-039). Thisapplication is also related to commonly assigned U.S. patent applicationSer. No. 10/205,018, filed on Jul. 25, 2002 (Attorney Docket NumberENP-040).

TECHNICAL FIELD

The present invention relates to novel semisynthetic macrolides havingantibacterial activity and useful in the treatment and prevention ofbacterial infections. More particularly, the invention relates to 6,11-4-carbon bridged erythromcyin derivatives, compositions containingsuch compounds and methods for using the same, as well as processes formaking such compounds.

BACKGROUND OF THE INVENTION

Erythromycins A through D, represented by formula (E) as illustratedbelow,

Erythromycin R^(a) R^(b) A —OH —CH3 B —H —CH3 C —OH —H D —H —Hare well-known and potent antibacterial agents, used widely to treat andprevent bacterial infection. As with other antibacterials, however,bacterial strains having resistance or insufficient susceptibility toerythromycin have been identified. Also, erythromycin A has only weakactivity against Gram-negative bacteria. Therefore, there is acontinuing need to identify new erythromycin derivative compounds whichpossess improved antibacterial activity, which have less potential fordeveloping resistance, which possess the desired Gram-negative activity,or which possess unexpected selectivity against target microorganisms.Consequently, numerous investigators have prepared chemical derivativesof erythromycin in an attempt to obtain analogs having modified orimproved profiles of antibiotic activity.

Kashimura et al. have disclosed 6-O-methylerythromycin derivativeshaving a tricyclic basic nuclear structure in European Application559896, published Nov. 11, 1991. Also, Asaka et al. have disclosed5-O-desoaminylerythronolide derivatives containing a tricyclic carbamatestructure in PCT Application WO 93/21200, published Apr. 22, 1992.

Recently erythromycin derivatives containing a variety of substituentsat the 6-0 position have been disclosed in U.S. Pat. Nos. 5,866,549 and6,075,011 as well as PCT Application WO00/78773. Furthermore, Ma, Or et.al. have described erythromycin derivatives with aryl groups tethered tothe C-6 position in J. Med Chem., 44, pp 4137-4156 (2001). U.S. Pat. No.6,046,171 and PCT application WO 99/21864, published May 6, 1999,disclose certain 6, 11-bridged erythromycin derivatives.

SUMMARY OF THE INVENTION

The present invention provides a novel class of C₆-C₁₁ bridged macrolidecompounds that possess antibacterial activity.

In one embodiment, the compounds of the present invention arerepresented by formula I, as illustrated below or their pharmaceuticallyacceptable salts, esters and prodrugs:

wherein

-   W is selected from the group consisting of:    -   (a) —CH₂—C(A)═C(B)—CH₂—;    -    wherein,        -   A and B are independently selected from the group consisting            of:            -   (i) hydrogen;            -   (ii) deuterium;            -   (iii) halogen;            -   (iv) R₁, wherein R₁ is selected from the group                consisting of:                -   a. C₁-C₆ alkyl, optionally substituted with one or                    more substituents selected from the group consisting                    of: halogen, aryl, substituted aryl, heteroaryl, and                    substituted heteroaryl;                -   b. C₂-C₆ alkenyl, optionally substituted with one or                    more substituents selected from the group consisting                    of: halogen, aryl, substituted aryl, heteroaryl, and                    substituted heteroaryl; and                -   c. C₂-C₆ alkynyl, optionally substituted with one or                    more substituents selected from the group consisting                    of: halogen, aryl, substituted aryl, heteroaryl, and                    substituted heteroaryl;            -   (v) R₂, wherein R₂ is selected from the group consisting                of:                -   a. aryl;                -   b. heteroaryl;                -   c. substituted aryl; and                -   d. substituted heteroaryl;            -   (vi) —(C₁-C₃-alkyl)-M-(C₁-C₃-alkyl)-R₂, wherein M=—O—,                —NH—, —N(CH₃)—, —NHC(O)—, —S(O)_(n)—, wherein n=0, 1 or                2, and R₂ is as previously defined;            -   (vii) —(C₁-C₃-alkyl)-M-R₂, wherein M and R₂ are as                previously defined;            -   (viii) —C(O)-J-R₃, wherein J is absent, O or S, and R₃                is H, R₁ or R₂, where R₁ and R₂ are as previously                defined; and            -   (ix) —C(O)—NR₁₁R₁₂, wherein R₁₁ and R₁₂ are each                independently selected from the group consisting of:                -   a. hydrogen;                -   b. C₁-C₆-alkyl, optionally substituted with one or                    more substituents selected from the group consisting                    of: halogen, aryl, substituted aryl, heteroaryl, and                    substituted heteroaryl;                -   C. C₂-C₆-alkenyl, optionally substituted with one or                    more substituents selected from the group consisting                    of: halogen, aryl, substituted aryl, heteroaryl, and                    substituted heteroaryl;                -   d. C₂-C₆-alkynyl, optionally substituted with one or                    more substituents selected from the group consisting                    of: halogen, aryl, substituted aryl, heteroaryl, and                    substituted heteroaryl; and                -   e. R₁₁ and R₁₂ taken together with the nitrogen atom                    to which they are connected form a 3- to 7-membered                    ring which may optionally contain one or more                    heterofunctions selected from the group consisting                    of: —O—, —NH—, —N(C₁-C₆-alkyl)-, —N(R₂)—,                    —S(O)_(N)—, wherein n and R₂ are as previously                    defined;    -   (b) —CH₂—CH(A)-C(B)═CH—, wherein A and B are as previously        defined;    -   (c) —CH₂—CH(E)-CH(G)-CH₂—;        -   wherein E and G are independently selected from the group            consisting of:            -   (i) A, wherein A is as previously defined;            -   (ii) —OH;            -   (iii) —OR^(P), wherein R^(P) is a hydroxy protecting                group;            -   (iv) —O—R₉, wherein R₉ is R₁ or R₂, and wherein R₁ and                R₂ are as previously defined;            -   (v) —S(O)_(n)R₉, wherein n and R₉ are as previously                defined;            -   (vi) —NHC(O)R₃, wherein R₃ is as previously defined;            -   (vii) —NHC(O)NR₁₁R₃, wherein R₁₁ and R₃ are as                previously defined;            -   (viii) —NHS(O)₂R₉, wherein R₉ is as previously defined;            -   (ix) —NHR₁₃, wherein R₁₃ is an amino protecting group;                and            -   (x) —NR₁₁R₁₂, wherein R₁₁ and R₁₂ are as previously                defined; (d)        -    wherein:        -   (i) -Q- is selected from the group consisting of: —O—;            —O—C(O)—CH(R₇)—; —N(R₇)—; —O—C(O)—N(R₇)—; —O—C(O)—O—;            —N(R₇)—N═N—; —C(R₇)═N—O—; and —CH(R₇)—N(R₈)—O—; wherein R₇            and R₈ are independently selected from R₃, wherein R₃ is as            previously defined; or        -   (ii) -Q- taken together with the two carbon atoms it is            attached to is selected from the group consisting of:            -   a. cycloalkylene;            -   b. cycloalkenylene; and            -   c. heterocycloalkylene; and    -   (e) —CH₂—C(R₄)(R₅)—CH₂—CH₂—;        -   wherein R₄ and R₅ taken together with the carbon atom to            which they are attached are selected from the group            consisting of:            -   (i) C═O;            -   (ii) C(OR₁)₂, wherein R₁ is as previously defined;            -   (iii) C(SR₁)₂, wherein R₁ is as previously defined;            -   (iv) C[—O(CH₂)_(m)]₂, wherein m is 2 or 3;            -   (v) C[—S(CH₂)_(m)]₂, wherein m is as previously defined,            -   (vi) C═CHR₃, wherein R₃ is as previously defined;            -   (vii) C═N—O—R₃, wherein R₃ is as previously defined;            -   (viii) C═NNHR₃, wherein R₃ is as previously defined;            -   (ix) C═NNHC(O)R₃, wherein R₃ is as previously defined;            -   (x) C═NNHC(O)NR₁₁R₃, wherein R₁₁ and R₃ are as                previously defined;            -   (xi) C═NNHS(O)₂R₉, wherein R₉ is as previously defined;            -   (xii) C═NNHR₁₃, wherein R₁₃ is as previously defined;                and            -   (xiii) C═NR₉, wherein R₉ is as previously defined;-   X and Y are:    -   (a) independently selected from the group consisting of:        -   (i) hydrogen;        -   (ii) deuterium;        -   (iii) —OH;        -   (iv) —OR^(P), wherein R^(P) is as previously defined; and        -   (v) —NR₁₄R₁₅, wherein R₁₄ and R₁₅ are each independently            selected from the group consisting of:            -   a. hydrogen;            -   b. C₁-C₁₂ alkyl, optionally substituted with one or more                substituents selected from the group consisting of                halogen, aryl, substituted aryl, heteroaryl and                substituted heteroaryl; and            -   c. R₁₄ and R₁₅, taken together with the nitrogen atom to                which they are attached form a 3 to 10 membered                heterocycloalkyl ring optionally substituted with one or                more hetero atoms selected from the group consisting of                O, S and N; or    -   (b) taken together with the carbon atom to which they are        attached are selected from the group consisting of:        -   (i) C═O;        -   (ii) C═NR₃, wherein R₃ is as previously defined;        -   (iii) C═NC(O)R₃, wherein R₃ is as previously defined;        -   (iv) C═N—OR₆, wherein R₆ is selected from the group            consisting of:            -   a. hydrogen;            -   b. —CH₂O(CH₂)₂OCH₃;            -   c. —CH₂O(CH₂O)_(n)CH₃, wherein n is as previously                defined;            -   d. C₁-C₁₂ alkyl, optionally substituted with one or more                substituents selected from the group consisting of                halogen, aryl, substituted aryl, heteroaryl and                substituted heteroaryl;            -   e. C₃-C₁₂ cycloalkyl;            -   f. C(O)—C₁-C₁₂ alkyl;            -   g. C(O)—(C₃-C₁₂ cycloalkyl);            -   h. C(O)—R₂, wherein R₂ is as previously defined; and            -   i. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and                R_(c) are each independently selected from the group                consisting of C1-C₁₋₂ alkyl, aryl and substituted aryl;                and        -   (v) C═N—O—C(R₁₆)(R₁₇)—O—R₁₈, wherein R₁₆ and R₁₇ taken            together with the carbon atom to which they are attached            form a C₃ to C₁₂ cycloalkyl group or each independently is            selected from the group consisting of: hydrogen, and C₁-C₁₂            alkyl; and R₁₈ is selected from the group consisting of:            -   a. hydrogen;            -   b. —CH₂O(CH₂)₂OCH₃;            -   c. —CH₂O(CH₂O)_(n)CH₃, wherein n is as previously                defined;            -   d. C₁-C₁₂ alkyl, optionally substituted with one or more                substituents selected from the group consisting of                halogen, aryl, substituted aryl, heteroaryl and                substituted heteroaryl;            -   e. C₃-C₁₂ cycloalkyl; and            -   f. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and                R_(c) are as previously defined;-   L is selected from the group consisting of:    -   (a) —CH(OH)CH₃;    -   (b) C₁-C₆ alkyl, optionally substituted with one or more        substituents selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl;    -   (c) C₂-C₆ alkenyl, optionally substituted with one or more        substituents selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; and    -   (d) C₂-C₆ alkynyl, optionally substituted with one or more        substituents selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl;-   K is selected from the group consisting of:    -   (a) R₁₀, wherein R₁₀ is selected from the group consisting of:        -   (i) hydrogen;        -   (ii) —OR^(P), wherein R^(P) is as previously defined;        -   (iii) —OR₃, wherein R₃ is as previously defined;        -   (iv) —OC(O)R₃, wherein R₃ is as previously defined;        -   (v) —OC(O)NR₁₁R₃, wherein R₁₁, and R₃ are as previously            defined; and        -   (vi) —S(O)_(n)R₉, wherein n and R₉ are as previously            defined; and    -   (b)    -    wherein R₃″ is hydrogen or methyl; R₄″ is hydrogen or R^(P),        wherein R^(P) is as previously defined; and-   R_(x) is hydrogen or R^(P), wherein R^(P) is as previously defined.

In another aspect of the present invention, pharmaceutical compositionsare disclosed that comprise a therapeutically effective amount of acompound of the invention in combination with a pharmaceuticallyacceptable carrier. The invention also includes a method of treatment ofantibacterial infections with such compositions. Suitable carriers andmethods of formulation are also disclosed. The compounds andcompositions of the present invention have antibacterial activity. In afurther aspect of the present invention, processes for the preparationof 6, 11-4 carbon bridged macrolides of formula I are provided.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is a compound represented by formulaI as illustrated above, or a pharmaceutically acceptable salt, ester orprodrug thereof.

A preferred group of compounds according to the present invention isrepresented by formula II as illustrated below, or a pharmaceuticallyacceptable salt, ester or prodrug thereof:

wherein A, B, X, Y, Rx and R₄″ are as previously defined.

Another preferred group of compounds according to the present inventionis represented by formula III as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein A, B, X, Y, R₁₀ and R_(x) are as previously defined.

Yet another preferred group of compounds according to the presentinvention is represented by formula IV as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

-   -   wherein A, B, X, Y, R_(x) and R₄ are as previously defined.

Another preferred group of compounds according to the present inventionis represented by formula V as illustrated below, or a pharmaceuticallyacceptable salt, ester or prodrug thereof:

wherein A, B, X, Y, R₁₀ and R_(x) are as previously defined.

Yet another preferred group of compounds according to the presentinvention is represented by formula VI as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

-   -   wherein A, B, X, Y, R_(x) and R₄ are as previously defined.

Another preferred group of compounds according to the present inventionis represented by formula VII as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein A, B, X, Y, R₁₀ and R_(x) are as previously defined.

Yet another preferred group of compounds according to the presentinvention is represented by formula VIII as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein Q, X, Y, R_(x) and R₄″ are as previously defined.

Another preferred group of compounds according to the present inventionis represented by formula IX as illustrated below, or a pharmaceuticallyacceptable salt, ester or prodrug thereof:

wherein Q, X, Y, R₁₀ and R_(x) are as previously defined.

Yet another preferred group of compounds according to the presentinvention is represented by formula X as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein E, G, X, Y, R_(x) and R₄″ are as previously defined.

Another preferred group of compounds according to the present inventionis represented by formula XI as illustrated below, or a pharmaceuticallyacceptable salt, ester or prodrug thereof:

wherein E, G, X, Y, R₁₀ and R_(x), are as previously defined.

Yet another preferred group of compounds according to the presentinvention is represented by formula XII as illustrated below, or apharmaceutically acceptable salt, ester

-   -   wherein X, Y, R₄, R₅, R_(x) and R₄ are as previously defined.

Another preferred group of compounds according to the present inventionis represented by formula XIII as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein X, Y, R₄, R₅, R₁₀ and R_(x) are as previously defined.

Yet another preferred group of compounds according to the presentinvention is represented by formula XIV as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

wherein X, Y, R₄, R₅, R_(x) and R₄ are as previously defined.

Another preferred group of compounds according to the present inventionis represented by formula XV as illustrated below, or a pharmaceuticallyacceptable salt, ester or prodrug thereof:

wherein X, Y, R₄, R₅, R₁₀ and R_(x) are as previously defined.

Another preferred embodiment of the invention are compounds representedby any of the above formulas I through XV wherein: X and Y takentogether with the carbon atom to which they are attached are selectedfrom the group consisting of: C═O, C═NR₃, C═N—O—R₆, C═N—C(O)R₃ andC═N—O—C(R₁₆)(R₁₇)—O—R₁₈ and R_(x) is hydrogen, where R₃, R₆, R₁₆, R₁₇and R₁₈ are as previously defined.

Yet another preferred embodiment of the invention are compoundsrepresented by any of the above formulas I through XV wherein: X and Ytaken together with the carbon atom to which they are attached areselected from the group consisting of: C═NC(O)R₃ andC═N—O—C(R₁₆)(R₁₇)—O—R₁₈; and Rx is hydrogen, where R₃ is methyl, R₁₈ ismethyl and R₁₆ and R₁₇ are each hydrogen.

Still yet another preferred embodiment of the invention are compoundsrepresented by formula I wherein L is —CH₂CH₃—.

Another preferred embodiment of the invention are compounds representedby any of the above formulas III, V, VII, IX, XI, XIII and XV whereinR₁₀=OH.

Representative compounds according to the invention include thoseselected from the group consisting of:

-   -   Compound of Formula (II): A=B═H; X and Y taken together with the        carbon atom they are attached to=C═N—OH; R_(x)=H and        R₄″=C(O)C₆H₅;    -   Compound of Formula (IV): A=3-quinolyl; B═H; X and Y taken        together with the carbon atom they are attached to=C═N—OH;        R_(x)=H and R₄″=C(O)CH₃;    -   Compound of Formula (II): A=C(O)OCH₃; B=H; X and Y taken        together with the carbon atom they are attached to=C═N—OH;        R_(x)=H and R₄″=C(O)C₆H₅;    -   Compound of Formula (II): A=B=H; X and Y taken together with the        carbon atom they are attached to=C═N—C(O)CH₃; R_(x)=H and        R₄″=C(O)C₆H₅;    -   Compound of Formula (VII): Q=—C(C₆H₅)═N—O—; X and Y taken        together with the carbon atom they are attached to=C═N—C(O)CH₃;        R_(x)=H and R₄″=C(O)C₆H₅;    -   Compound of Formula (VIII): Q=—O—C(O)—O—; X and Y taken together        with the carbon atom they are attached to=C═N—C(O)CH₃; R_(x)=H        and R₄″=C(O)C₆H₅;    -   Compound of Formula (VIII): Q=—O—; X and Y taken together with        the carbon atom they are attached to=C═N—C(O)CH₃; R_(x)=H and        R₄″=C(O)C₆H₅;    -   Compound of Formula (VIII): Q=—O—; X and Y taken together with        the carbon atom they are attached to=C═N—C(O)CH₃; R_(x)=H and        R₄″=H;    -   Compound of Formula (II): A=B=H; X and Y taken together with the        carbon atom they are attached to=C═NC(O)CH₂OCH₃; R_(x)=H and        R₄″=C(O)C₆H₅;    -   Compound of Formula (II): A=B=H; X and Y taken together with the        carbon atom they are attached to=C═N—C(O)—CH₂OCH₃; R_(x)=H and        R₄″=H;    -   Compound of Formula (IV): A=3-quinolyl; B=H; X and Y taken        together with the carbon atom they are attached to=C═N—C(O)CH₃;        R_(x)=H and R₄″=C(O)C₆H₅;    -   Compound of Formula (IV): A=3-quinolyl; B=H; X and Y taken        together with the carbon atom they are attached to=C═N—C(O)CH₃;        R_(x)=H and R₄″=H;    -   Compound of Formula (II): A=C(CH═CH—C₆H₅); B=H; X and Y taken        together with the carbon atom they are attached to=C═N—C(O)CH₃;        R_(x)=H and R₄″=C(O)C₆H₅;    -   Compound of Formula (II): A=C(CH═CH—C₆H₅); B=H; X and Y taken        together with the carbon atom they are attached to=C═NC(O)CH₃;        R_(x)=H and R₄″=H;    -   Compound of Formula (II): A=C(CH═CH—C₆H₅); B=H; X and Y taken        together with the carbon atom they are attached to=C═N—C(O)CH₃;        R_(x)=H and R₄″=C(O)C₆H₅;    -   Compound of Formula (II): A=C(CH═CH—C₆H₅); B=H; X and Y taken        together with the carbon atom they are attached to=C═NC(O)CH₃;        R_(x)=H and R₄″=H;    -   Compound of Formula (II): A=H; B=H; X and Y taken together with        the carbon atom they are attached to=C═N—Ac; R_(x)=H and R₄″=H;    -   Compound of Formula (II): A=C(O)—OH; B=H; X and Y taken together        with the carbon atom they are attached to=C═N—OH; R_(x)=H and        R₄″=H; and

Compound of Formula (II): A=B=H, X and Y taken together with the carbonatom they are attached to=C═O, R_(x)=H and R₄″=C(O)CH₃.

Definitions

The terms “C₁-C₃ alkyl,” “C₁-C₆ alkyl” or “C₁-C₁₂ alkyl,” as usedherein, refer to saturated, straight- or branched-chain hydrocarbonradicals containing between one and three, one and twelve, or one andsix carbon atoms, respectively. Examples of C₁-C₃ alkyl radicals includemethyl, ethyl, propyl and isopropyl radicals; examples of C₁-C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl radicals; andexamples of C₁-C₁₂ alkyl radicals include, but are not limited to,ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecyl radicals.

The term “substituted alkyl” or “alkyl substituent” refers to an alkylgroup substituted by, for example, one to four substituents, such as,halo, phenyl, substituted phenyl, heterocyclo, trifluoromethyl,trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy, heterocylooxy, oxo,alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino,aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines inwhich the 2 amino substituents are selected from alkyl, aryl or aralkyl,alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino,substituted arylamino, substituted aralkanoylamino, thiol, alkylthio,arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono,arylthiono, aralkylthiono, alkysulfonyl, arylsulfonyl, aralkylsulfonyl,sulfonamido (e.g. SO₂NH₂), substituted sulfonamido, nitro, cyano,carbamyl (e.g. CONH₂), substituted carbamyl (e.g. CONH alkyl, CONH aryl,CONH aralkyl or cases where there are two substituents on the nitrogenselected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substitutedaryl, guanidine and heterocyclos, such as, indolyl, imidazolyl, furyl,thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like. Where,if noted above, the substituent is further substituted, it will be withhalogen, alkyl, alkoxy, aryl or aralkyl.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl.

The term “alkylene” denotes a divalent group derived from a straight orbranched chain saturated hydrocarbon by the removal of two hydrogenatoms, for example, methylene, 1,2-ethylene, 1,1-ethylene,1,3-propylene, and the like.

The terms “C₂-C₁₂ alkenyl” or “C₂-C₆ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, and the like.

The term “alkenylene” denotes a divalent group derived from an alkenylgroup as defined previously by the removal a second hydrogen atom,containing from two to twelve carbon atoms and having at least onecarbon-carbon double bond, for example, 1,2-ethenyl, 1,2-propylene,1,4-butenyl, 1-methyl-but-1-en-1,4-yl, and the like.

The terms “C₂-C₁₂ alkynyl” or “C₂-C₆ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbontriple bond by the removal of two hydrogen atoms. Representative alkynylgroups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “haloalkyl” denotes an alkyl group, as defined above, havingone, two or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term “aryl,” as used herein, refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyland the like. Aryl groups (including bicyclic aryl groups) can beunsubstituted or substituted with one, two or three substitutentsindependently selected from loweralkyl, substituted loweralkyl,haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino,acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde,carboxy, alkoxycarbonyl and carboxamide. In addition, substituted arylgroups include tetrafluorophenyl and pentafluorophenyl.

The term “arylene” denotes a divalent group derived from an aryl moietyas defined previously by the removal of a second hydrogen atom. Arylenegroups include, for example, 1,2-phenyl, 1,3-phenyl, 1,4-phenyl,1,2-naphthyl, 1,4-naphthyl, 1,6-naphthyl, and the like.

The term “substituted aryl,” as used herein, refers to an aryl group, asdefined herein, substituted by independent replacement of one, two orthree of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO₂, CN,C(O)—C₁-C₆-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl,CO₂-heteroaryl, CONH₂, CONH-C₁-C₆-alkyl, CONH-aryl, CONH-heteroaryl,OC(O)—C₁-C₆-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl,OCO₂-heteroaryl, OCONH₂, OCONH—C₁-C₆-alkyl, OCONH-aryl,OCONH-heteroaryl, NHC(O)—C₁-C₆-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl,NHCO₂-alkyl, NHCO2-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—C₁-C₆-alkyl,NHCONH-aryl, NHCONH-heteroaryl, SO₂—C₁-C₆-alkyl, SO₂-aryl,SO₂-heteroaryl, SO₂NH₂, SO₂NH—C₁-C₆-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl,C₁-C₆-alkyl, C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHCl₂, CH₂OH, CH₂CH₂OH,CH₂NH₂, CH₂SO₂CH₃, aryl, heteroaryl, benzyl, benzyloxy, aryloxy,heteroaryloxy, C₁-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino,benzylamino, arylamino, heteroarylamino, C₁-C₃-alkylamino, thio,aryl-thio, heteroarylthio, benzyl-thio, C₁-C₆-alkyl-thio, ormethylthiomethyl.

The term “substituted arylene” as used herein refers to an arylene groupas defined herein substituted by independent replacement of one, two orthree of the hydrogen atoms thereon with halo, hydroxyl, cyano,C₁-C₃-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy substituted with aryl,haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, acylamino,mercapto, nitro, carboxaldehyde, carboxyl, alkoxycarbonyl andcarboxamide. In addition, any one substituent may be an aryl,heteroaryl, or heterocycloalkyl group. Also, substituted aryl groupsinclude tetrafluorophenyl and pentafluorophenyl.

The term “heteroaryl,” as used herein, refers to a cyclic aromaticradical having from five to ten ring atoms of which one ring atom isselected from S, O and N; zero, one or two ring atoms are additionalheteroatoms independently selected from S, O and N; and the remainingring atoms are carbon, the radical being joined to the rest of themolecule via any of the ring atoms, such as, for example, pyridinyl,pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,quinolinyl, isoquinolinyl, and the like.

The term “heteroarylene” denotes a divalent group derived from aheteroaryl moiety as defined previously by the removal a second hydrogenatom. Heteroarylene groups include, for example, 2,3-pyridyl,2,4-pyridyl, 2,6-pyridyl, 2,3-quinolyl, 2,4-quinolyl, 2,6-quinolyl,1,4-isoquinolyl, 1,6-isoquinolyl, and the like.

The term “substituted heteroaryl,” as used herein, refers to aheteroaryl group as defined herein, substituted by independentreplacement of one, two or three of the hydrogen atoms thereon with F,Cl, Br, I, OH, NO₂, CN, C(O)—C₁-C₆-alkyl, C(O)-aryl, C(O)-heteroaryl,CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂, CONH—C₁-C₆-alkyl, CONH-aryl,CONH-heteroaryl, OC(O)—C₁-C₆-alkyl, OC(O)-aryl, OC(O)-heteroaryl,OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl, OCONH₂, OCONH—C₁-C₆-alkyl,OCONH-aryl, OCONH-heteroaryl, NHC(O)—C₁-C₆-alkyl, NHC(O)-aryl,NHC(O)-heteroaryl, NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂,NHCONH—C₁-C₆-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO₂—C₁-C₆-alkyl,SO₂-aryl, SO₂-heteroaryl, SO₂NH₂, SO₂NH—C₁-C₆-alkyl, SO₂NH-aryl,SO₂NH-heteroaryl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHCl₂,CH₂OH, CH₂CH₂OH, CH₂NH₂, CH₂SO₂CH₃, aryl, heteroaryl, benzyl, benzyloxy,aryloxy, heteroaryloxy, C₁-C₆-alkoxy, methoxymethoxy, methoxyethoxy,amino, benzylamino, arylamino, heteroarylamino, C₁-C₃-alkyl-amino, thio,aryl-thio, heteroarylthio, benzyl-thio, C₁-C₆-alkyl-thio, ormethylthiomethyl.

The term “substituted heteroarylene,” as used herein, refers to aheteroarylene group as defined herein substituted by independentreplacement of one, two or three, of the hydrogen atoms thereon with Cl,Br, F, I, OH, CN, C₁-C₃-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy substitutedwith aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino,mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and the like.In addition, any one substituent may be an aryl, heteroaryl, orheterocycloalkyl group.

The term “C₃-C₁₂-cycloalkyl” or “cycloalkyl,” as used herein, refers toa monovalent group derived from a monocyclic or bicyclic saturatedcarbocyclic ring compound by the removal of a single hydrogen atom.Examples include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo [2.2.2]octyl.

The term “heterocycloalkyl,” as used herein, refers to a non-aromatic 3-to 7-membered ring or a bi- or tri-cyclic group comprising fusedsix-membered rings having between one and three heteroatomsindependently selected from oxygen, sulfur and nitrogen, wherein (i)each 5-membered ring has 0 to 1 double bonds and each 6-membered ringhas 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms mayoptionally be oxidized, (iii) the nitrogen heteroatom may optionally bequaternized, and (iv) any of the above heterocyclic rings may be fusedto a benzene ring. Representative heterocycles include, but are notlimited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

The term “cycloalkylene” refers to a divalent cycloalkyl moiety with twohydrogen atoms removed—one each from two adjacent carbon atoms—derivedby the removal of the two hydrogen atoms from a cycloalkyl group aspreviously defined that is optionally substituted, or from saturatedcyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and3 to 7 carbons per ring which may be further fused to an unsaturatedC₃-C₇ carbocyclic ring. Exemplary cycloalkyl groups from which thecycloalkylene groups can be derived include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,cyclododecyl, and adamantly. Exemplary substituents include one or morealkyl, aryl, heteroaryl groups as described above, or one or more groupsdescribed above as alkyl substituents.

The term “cycloalkenylene” refers to a divalent cycloalkenyl moiety withtwo hydrogen atoms removed—one each from two adjacent carbonatoms—derived by the removal of the two hydrogen atoms from acycloalkenyl group that contains one or more unsaturated double bondsoptionally substituted, or from unsaturated cyclic ring systems,preferably containing 1 to 3 rings and 3 to 7 carbons per ring which maybe further fused with an unsaturated C3-C7 carbocyclic ring. Exemplarycycloalkenyl groups from which the cycloalkenylene groups can be derivedinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, andthe like. Exemplary substituents include one or more alkyl, aryl,heteroaryl groups as described above, or one or more groups describedabove as alkyl substituents.

The term “heterocycloalkylene” refers to a divalent heterocyclic moietywith two hydrogen atoms removed—one each from two adjacent carbonatoms—derived by the removal of the two hydrogen atoms from aheterocycloalkyl group previously defined that is optionallysubstituted, or from a fully saturated or unsaturated, nonaromaticcyclic group which may be further fused with or substituted with anaromatic ring, for example, which is a 3 to 7 membered monocyclic, 7 to11 membered bicyclic, or 10 to 15 membered tricyclic ring system, whichhas at least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized and the nitrogen heteroatoms may also optionally bequaternized. The heterocyclic group may be attached at any heteroatom orcarbon atom. Exemplary monocyclic heterocyclic groups from which theheterocycloalkylene groups can be derived include pyrrolidinyl,pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolidinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl,azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, and triazolyl, and the like. Exemplary bicyclicheterocyclic groups from which the heterocycloalkylene groups can bederived include benzothiazolyl, benzoxazolyl, benzothienyl,quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl,chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,1-b]pyridinyl or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazollinyl, (such as 3,4-dihydro-4-oxo-quinazolinyl),benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl,benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl, and the like. Exemplary substituents include one or morealkyl, aryl or heteroaryl groups as described above or one or moregroups described above as alkyl substituents. Also included are smallerheterocyclics, such as epoxides and aziridines.

The term “heteroatoms” includes, but is not limited to, oxygen, sulfurand nitrogen.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,neopentoxy and n-hexoxy.

The term “C₁-C₃-alkyl-amino,” as used herein, refers to one or twoC₁-C₃-alkyl groups, as previously defined, attached to the parentmolecular moiety through a nitrogen atom. Examples of C₁-C₃-alkyl-aminoinclude, but are not limited to methylamino, dimethylamino, ethylamino,diethylamino, and propylamino.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl) where C₁-C₁₂ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl) (C₁-C₁₂ alkyl), where C₁-C₁₂ alkyl is as previously defined.Examples of dialkylaminoinclude, but are not limited to, dimethylamino,diethylamino, methylethylamino, piperidino, and the like.

The term “alkoxycarbonyl” represents an ester group, i.e. an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The term “carboxaldehyde,” as used herein, refers to a group of formula—CHO.

The term “carboxy,” as used herein, refers to a group of formula —COOH.

The term “carboxamide,” as used herein, refers to a group of formula—C(O)NH(C₁-C₁₂ alkyl) or —C(O)N(C₁-C₁₂ alkyl) (C₁-C₁₂ alkyl).

“Hydroxy protecting group,” as used herein, refers to an easilyremovable group such as is known in the art to protect a hydroxy groupagainst undesirable reaction during synthetic procedures and to beselectively removable. The use of hydroxy-protecting groups is wellknown in the art for protecting groups against undesirable reactionsduring a synthetic procedure and many such protecting groups are known,cf. for example, T. H. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis. 3rd edition, John Wiley & Sons, New York (1999).Examples of hydroxy protecting groups include, but are not limited to,methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acylsubstituted with an aromatic group and the like.

The term “protected hydroxy” refers to a hydroxy group protected with ahydroxy protecting group, as defined above, including benzoyl, acetyl,trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.

“Amino protecting group,” as used herein, refers to an easily removablegroup such as is known in the art to protect an amino group againstundesirable reaction during synthetic procedures and to be selectivelyremovable. The use of amino-protecting groups is well known in the artfor protecting groups against undesirable reactions during a syntheticprocedure and many such protecting groups are known, cf. for example, T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis. 3rdedition, John Wiley & Sons, New York (1999). Examples of aminoprotecting groups include, but are not limited to, 9-fluorenylmethylcarbamate, benzylcarbonate, tert-butylcarbonate, benzyl, p-toluenesulfonyl, acyl and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. 1, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protic solvent” or “protogenic organic solvent,” as usedherein, refers to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of protogenic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. 11, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

Numerous asymmetric centers may exist in the compounds of the presentinvention. Except where otherwise noted, the present inventioncontemplates the various stereoisomers and mixtures thereof.Accordingly, whenever a bond is represented by a wavy line, it isintended that a mixture of stereo-orientations or an individual isomerof assigned or unassigned orientation may be present.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein byreference. The salts can be prepared in situ during the final isolationand purification of the compounds of the invention, or separately byreacting the free base function with a suitable organic acid. Examplesof pharmaceutically acceptable, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

In addition, zwitterions (“inner salts”) may be formed from thecompounds of the present invention.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. The term “prodrug” refers to compounds that arerapidly transformed in vivo to yield the parent compound of the aboveformula, for example by hydrolysis in blood. A thorough discussions isprovided in T. Higuchi and V. Stella, “Pro-drugs as Novel DeliverySystems, Vol. 14 of the ACS Symposium Series, and in Edward B. Roche,ed., “Bioreversible Carriers in Drug Design”, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and    Application of Prodrugs,” by H. Bundgaard, p. 113-191 (1991);-   c) H. Bundgaard, et al., Advanced Drug Delivery Reviews, 8, 1-38    (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1998); and-   e) N. Kakeya, et al., Chem Phar Bull, 32, 692 (1984).

It should further be understood that solvates (e.g., hydrates) of thecompounds of the present invention are also within the scope of thepresent invention. Methods of solvation are generally known in the art.

Antibacterial Activity

Susceptibility tests can be used to quantitatively measure the in vitroactivity of an antimicrobial agent against a given bacterial isolate.Compounds were tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) wasdetermined in 96 well microfiter plates utilizing the appropriateMueller Hinton Broth medium (CAMHB) for the observed bacterial isolates.Antimicrobial agents were serially diluted (2-fold) in DMSO to produce aconcentration range from about 64 μg/ml to about 0.03 μg/ml. The dilutedcompounds (2 μl/well) were then transferred into sterile, uninoculatedCAMHB (0.2 mL) by use of a 96 fixed tip-pipetting station. The inoculumfor each bacterial strain was standardized to 5×10⁵ CFU/mL by opticalcomparison to a 0.5 McFarland turbidity standard. The plates wereinoculated with 10 μl/well of adjusted bacterial inoculum. The 96 wellplates were covered and incubated at 35+/−2° C. for 24 hours in ambientair environment. Following incubation, plate wells were visuallyexamined by Optical Density measurement for the presence of growth(turbidity). The lowest concentration of an antimicrobial agent at whichno visible growth occurs was defined as the MIC. The compounds of theinvention generally demonstrated an MIC in the range from about 64 μg/mlto about 0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A4 protocol, published by the National Committee forClinical Laboratory Standards (NCCLS).

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminunhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate. Coloring agents, releasing agents, coating agents,sweetening, flavoring and perfuming agents, preservatives andantioxidants can also be present in the composition, according to thejudgment of the formulator. The pharmaceutical compositions of thisinvention can be administered to humans and other animals orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, or drops),buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such asmagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention,bacterial infections are treated or prevented in a patient such as ahuman or other animals by administering to the patient a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired result. By a“therapeutically effective amount” of a compound of the invention ismeant a sufficient amount of the compound to treat bacterial infections,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment of from about 10mg to about 1000 mg of the compound(s) of this invention per day insingle or multiple doses.

The pharmaceutical compositions of this invention can be administered tofish by blending them in the fish feed to be administered orally or maybe dissolved in water in which sick fish are placed to swim around (amethod using a so-called “medicated bath”). The dosage for the treatmentof fish differs depending upon the purpose of administration (preventionor cure of disease) and type, size and extent of infection of the fishto be treated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg,per kg of body weight of fish may be administered per day, either at onetime or divided into several times. It will be recognized that theabove-specified dosage is only a general range which may be reduced orincreased depending upon the age, body weight, condition of disease,etc. of the fish.

Abbreviations

Abbreviations which have been used in the description of the schemes andthe examples are as follows: AIBN for azobisisobutyronitrile; Boc fortert-Butoxycarbonyl; BSA for bis(trimethylsilyl)acetamide; Bu₃SnH fortributyltin hydride; CDI for carbonyldiimidazole; dba fordibenzylideneacetone; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAPfor 4-N,N-dimethylamino-pyridine; DCC for 1,3-dicyclohexylcarbodiimide;DEAD for diethylazodicarboxylate; DMF for dimethyl formamide; DMSO fordimethylsulfoxide; DPPA for diphenylphosphoryl azide; dppb for1,4-bis(diphenylphosphino)butane; dppe for1,2-bis(diphenylphosphino)ethane; EDC for1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EtOAc for ethyl acetate;HMDS for 1,1,1,3,3,3-Hexamethyldisilazane; KHMDS for potassiumbis(trimethylsilyl)amide; m-CPBA for meta-chloroperbenzoic acid; MeOHfor methanol; MOMCl for methoxymethylchloride; NaHMDS for sodiumbis(trimethylsilyl)amide; NaN(TMS)₂ for sodium bis(trimethylsilyl)amide;NCS for N-Chlorosuccinimide; NMO for N-methylmorpholine N-oxide; PCC forpyridinium chlorochromate; PDC for pyridinium dichromate; Ph for phenyl;TBS for tert-butyl dimethyl silyl; TEA for triethylamine; TBF fortetrahydrofuran; TPP for triphenylphosphine; TBAF for tetra-n-butylammonium fluoride; TFA for trifluoroacetic acid; TMS for trimethylsilyl; TPAP for tetrapropylammonium perruthenate; Ac for acetyl and Bzfor benzoyl.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes (schemes1-12) that illustrate the methods by which the compounds of theinvention may be prepared. The groups A, B, Rx, R₃, R₆, R^(P), X and Yare as defined previously herein, unless otherwise noted below. As usedin the schemes and examples, the group “V” taken together with thecarbon atom it is attached to is selected from the group: C═O, C═NR₃,C═N—O—R₆, C═NC(O)R₃ and C═N—O—C(R₁₆)(R₁₇)—O—R₁₈, where R₃, R₆, R₁₆, R₁₇and R₁₈ are as previously defined herein.

Compounds of formula (1-2) or a1-4), which are useful as the startingmaterials for the preparation of compounds of the present invention, maybe synthesized as detailed in schemes 1 and 3 below. An erythromycinderivative (1-1) is prepared from erythromycin using the proceduresdescribed in U.S. Pat. Nos. 4,990,602; 4,331,803; 4,680,386; and4,670,549 which are incorporated herein by reference. Also incorporatedby reference is European Patent Application EP 260,938. The proceduresfor preparing the 6, 11-bridged compounds of the present invention aredescribed in U.S. patent application Ser. Nos. 10/144,396 and10/144,558, filed on May 13, 2002, which are herein incorporated byreference in their entirety. The C-9 position (X, Y) can be furtherderivatized with suitable procedures that are well-known in the art andthose mentioned in PCT publications: WO 00/62783 and WO 98/38199 as wellas publications: “Synthetic Modifications of the Erythromycin AMacrolactone: Effects on Biological Activity,” Lartey, P. A. and Perun,T. J., Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol.13, 1993, and “Recent developments in 14- and 15-membered macrolides,”Chu, Daniel T. W., Section Review: Anti-infectives, Exp. Opin. Invest.Drugs 1995, 4(2), page 65-94, which are herein incorporated by referencein their entirety.

A preferred intermediate for the preparation of compounds represented byformula I is a compound represented by formula XVI as illustrated below:

wherein R₆ and R_(x) are as previously defined and R₄″ is a hydroxyprotecting group.

A second preferred intermediate for the preparation of compoundsrepresented by formula I is a compound represented by formula XVII asillustrated below:

wherein A, B, R_(x) and R₄″ are as previously defined; V taken togetherwith the carbon atom it is attached to is selected from the groups: C═O,C═NR₃, C═N—O—R₆, C═NC(O)R₃ and C═N—O—C(R₁₆)(R₁₇)—O—R₁₈, where R₃, R₆,R₁₆, R₁₇ and R₁₈ are as previously defined; and R^(P) ₁ is H or R^(P),where R^(P) is as previously defined.

A synthetic method of the present invention, as illustrated in scheme 1,involves preparing a compound of formula (1-4) by reacting a compound offormula (1-2) with a suitable alkylating agent.

In accordance with scheme 1, the 9-keto group of the erythromycinbackbone can be initially converted into an oxime by methods describedin U.S. Pat. No. 4,990,602, followed by the protection of the 2′- and4″-hydroxy groups with R_(x) and R₄″ respectively, and if desired, theresulting oxime group can be further derivatized with R₆ to obtain thecompounds of formula (1-2).

The 2′- and 4″-hydroxy groups are protected by reaction with suitablehydroxy protecting agents in an aprotic solvent. Typical hydroxyprotecting reagents include, but are not limited to, acetylating agents,silylating agents, acid anhydrides, and the like. Examples of hydroxyprotecting reagents are, for example, acetyl chloride, acetic anhydride,benzoyl chloride, benzoic anhydride, benzyl chloroformate,hexamethyldisilazane, and trialkylsilyl chlorides.

Examples of aprotic solvents are dichloromethane, chloroform,tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, a mixture thereof or a mixture of one of these solvents withether, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-dichloroethane,acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents donot adversely affect the reaction. Preferably, the solvent is selectedfrom dichloromethane, chloroform, N,N-dimethylformamide,tetrahydrofuran, N-methylpyrrolidinone or mixtures thereof. A morethorough discussion of solvents and conditions for protecting thehydroxy group can be found in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis” 3^(rd) ed., John Wiley & Son,Inc, 1999, which is incorporated by reference herein.

Protection of the 2′- and 4″-hydroxy groups may be accomplishedsequentially or simultaneously to provide compound (1-2) where R_(x)and/or R₄″ can be, for example, but not limited to, acetyl, benzoyl,trimethylsilyl, and the like. Preferred protecting groups includeacetyl, benzoyl, and trimethylsilyl. A particularly preferred group forprotecting the hydroxy and oxime groups is the acetyl protecting group,wherein R_(x)=R₄″=R₆=Ac.

Acetylation of the hydroxy group is typically accomplished by treatingthe compound (1-1) with an acetylating reagent, for example, aceticanhydride or acetyl chloride.

The erythromycin derivative of formula (1-2) is then reacted with analkylating agent of the formula:

where R₁₉ is C₁-C₁₂-alkyl.

The reaction is carried out in an aprotic solvent with a palladiumcatalyst [Pd(0) or Pd(II)] with a phosphorus ligand such as, forexample, dppb, dppe, and the like, in aprotic solvents to providecompound (1-4) from about room temperature to about 100° C., preferablyat elevated temperature, for example, at or above 50° C. (see (a) Trost,B. M. Angew. Chem. Int. Ed. Eng. 1989, 28, 1179; (b) Heck, PalladiumReagents in Organic Synthesis, Academic Press: New York, 1985, Chapter1; (c) Tsuji, Tetrahedron Lett. 1992, 33, 2987; (d) Beller et al. Angew.Chem. Int. Ed. Engl., 1995, 34 (17), 1848, etc.). Suitable aproticsolvents include, but are not limited to, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone,hexamethylphosphoric triamide, 1,2-dimethoxyethane, methyl-tert-butylether, heptane, acetonitrile, isopropyl acetate and ethyl acetate. Themost preferred solvents are tetrahydrofuran or toluene.

The palladium catalyst suitable in the present invention can be selectedfrom, but not limited to, the group consisting of palladium (II)acetate, tetrakis (triphenylphosphine) palladium (0),tris(dibenzylideneacetone) dipalladium,tetradi(benzylideneacetone)dipalladium and the like. Palladium on carbonand palladium (II) halide catalysts are less preferred than otherpalladium catalysts for this process.

Phosphorus ligands useful in the present invention include, but are notlimited to, triphenylphosphine, bis(diphenylphosphino)methane,bis(diphenylphosphino)ethane, bis(diphenylphosphino)propane,1,4-bis(diphenylphosphino)butane, bis(diphenylphosphino)pentane, andtir(o-tolyl)phosphine, and the like.

The alkylating agents useful in the present invention are di-carbonateshaving the formula (1-3), as previously described. The preferredalkylating agents are those wherein R₁₉ is a tert-butyl, isopropyl orisobutyl group. The alkylating reagents are prepared by reaction of adi-ol with a wide variety of compounds for incorporating thedi-carbonate moiety. The compounds include, but are not limited to,tert-butyl chloroformate, di-tert-butyl dicarbonate,1-(tert-butoxycarbonyl) imidazole etc. The reaction is carried out inthe presence of an organic or an inorganic base such as, for example,but not limited to, sodium hydride, potassium hydride, potassiumtert-butoxide, potassium hydroxide, ammonium hydroxide, sodiumcarbonate, potassium carbonate, ammonium carbonate, KHMDS, DMAP,pyridine, triethylamine, and the like, in an aprotic solvent such asTHF, DMSO, DMF, dioxane, and the like, or mixtures thereof. Thetemperature for the reaction ranges from about −20° C. to about 60° C.,preferably from about −30° C. to about 30° C.

The conversion of the di-ol into the di-carbonate can also be done bytreating the di-ol with phosgene or triphosgene to prepare thechloroformate derivative of the di-ol. The di-chloroformate derivativeis then converted into the di-carbonate by the methods described inCotarca, L., Delogu, P., Nardelli, A., Sunijic, V, Synthesis, 1996, 553,incorporated by reference herein in its entirety. The reaction can becarried out in a variety of organic solvents such as dichloromethane,toluene, diethyl ether, ethyl acetate, chloroform, and the like, in thepresence of a base as previously described herein. The temperatureconditions can vary from about −30° C. to about 60° C. The reactiontakes from about 1 hour to about 12 hours, preferably from about 2 toabout 6 hours, to run to completion.

The cladinose moiety of macrolide (1-4) is removed by mild acidhydrolysis to give compounds of formula (2-1). Representative acidsinclude, but are not limited to, hydrochloric acid, sulfuric acid,perchloric acid, chloroacetic acid, dichloroacetic acid, trifluoroaceticacid, and the like. Suitable solvents for the reaction include, but arenot limited to, methanol, ethanol, isopropanol, butanol and the like.Reaction times range from about 0.5 hours to about 24 hours. Thereaction temperature is preferably from about −10° C. to about 80° C.Simultaneous deprotection, of both the oxime and the 2′ hydroxy group,can be accomplished similarly.

Conditions for deprotection include, but are not limited to, treatingwith an alcoholic solvent from room temperature to reflux, or treatmentwith an amine, preferably a primary amine, for example, propylamine,butylamine, and the like. Alcoholic solvents preferred for thedeprotection are methanol and ethanol. A more thorough discussion of theprocedures, reagents and conditions for removing protecting groups isdescribed in the literature, for example, by T. W. Greene and P. G. M.Wuts in “Protective Groups in Organic Synthesis” 3^(rd) ed., John Wiley& Son, Inc, 1999, which is incorporated by reference herein.

Compounds of formula (1-4) where R₆ is an acetyl group can be convertedinto the corresponding imine as outlined in Scheme 3. Selectivedeprotection of the oxime is typically accomplished via alkalinehydrolysis in protic solvents. Representative bases include lithiumhydroxide, sodium hydroxide, potassium hydroxide, and the like. Solventswhich are suitable include, but are not limited to, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, isopropanol, ethanol, butanol, waterand mixtures thereof. The reaction temperature is preferably 0° to 35°C., and reaction time is preferably 0.5 to 24 hours.

Deoximation of compounds of formula (1-4) where R₆ is H can be doneunder reducing conditions to give the macrolide imine of formula (3-2).Many reducing agents can be used to effect this transformationincluding, but not limited to, lithium aluminum hydride, titaniumtrichloride, sodium cyanoborohydride, borane, sodium nitrite, sulfuroxides such as, for example, sodium pyrosulfate, sodium thiosulfate,sodium sulfate, sodium sulfite, sodium hydrogensulfite, sodiummetabisulfite, sodium dithionate, potassium thiosulfate, potassiummetabisulfite, and the like (also see, (a) Greene (op. cit.); (b) J.March, Advanced Organic Chemistry, 4^(th) ed., Wiley & Son, Inc., 1992,9-51, and references therein). For example, when appropriate thereaction is carried out under acidic conditions in protic solvents.Representative acids include, but are not limited to, acetic acid,citric acid, oxalic acid, tartaric acid, formic acid, dilutehydrochloric acid, dilute phosphoric acid, dilute sulfuric acid, and thelike. Suitable protic solvents include, but are not limited to, mixturesof water and methanol, ethanol, isopropanol, butanol etc. The reactionis carried out at a temperature from about room temperature to about110° C., for about 1 to about 24 hours.

An example of a method for the reduction of oximes to the correspondingimine uses a sulfite reducing agent such as sodium hydrogensulfite ortitanium trichloride, under acidic conditions in protic solvents.Representative acids that may be used include, but are not limited to,acetic acid, formic acid, dilute hydrochloric acid, dilute phosphoricacid, dilute sulfuric acid, and the like. Suitable protic solventsinclude, but are not limited to, mixtures of water and methanol,ethanol, isopropanol, or butanol. The reaction is typically carried outfrom about 25° C. to about 110° C., preferably for about 1 to about 10hours.

Another method of the present invention, as illustrated in Scheme 4,involves a procedure for the acylation of imines of the formula (3-2).The imine in the 9 position of compounds of formula (3-2) can beacylated with an acylating agent such as, for example, R₃C(O)T, where Tis a halide or —OH, or (R₃C(O))₂O, where R₃ is as previously definedusing standard acylating conditions to give compounds of formula (4-1).For example, imines of formula (3-2) can be acylated under basicconditions using a suitable acylating agent in an aprotic solvent, withor without an activation agent. Typical acylating agents include, butare not limited to, acetyl chloride, acetic anhydride, benzoyl chloride,benzoic anhydride, benzyl chloroformate, and the like. Examples ofactivation agents for acids include, but are not limited to, DCC, EDC,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc.

Typical bases useful in acylation reactions include, but are not limitedto, pyridine, DMAP, triethylamine, diisopropyl ethylamine, N-methylmorpholine, N-methyl pyrrolidine, 2,6-lutidine,1,8-diazabicyclo[5.4.0]undec-7-ene, and the like (see, T. W. Greene andP. G. M. Wuts in “Protective Groups in Organic Synthesis” 3 rd ed., JohnWiley & Son, Inc, 1999, and references therein). Compounds of formula(2-3) can be further deprotected as described in scheme 1 to obtain the2′ free hydroxy group and the 9-position oxime.

Stepwise formation of the 6, 11-4-carbon bridged macrolides is alsopossible as outlined in scheme 5. In a similar manner as previouslydescribed, the procedure involves reacting a compound of formula (1-2)with a suitable alkylating agent. As before, the erythromycin derivativeof formula (1-2) is reacted with an alkylating agent of the formula:

where R₁₉ is C₁-C₁₂-alkyl and A and B are as previously defined andR^(P) ₁ is H or R^(P) where R^(P) is as previously defined.

As discussed previously in scheme 1, compounds of formula (1-2) may beconverted to compounds of formula (5-2) using a palladium catalyst witha phosphorous ligand in an aprotic solvent, preferably at elevatedtemperature, more preferably at or above 50° C. The preferred solventsare tetrahydrofuran and toluene.

The alkylating agents useful in the process of the invention are mixedsilyl ether carbonates. Generally, the alkylating agents have theformula (5-1), as previously described. The preferred alkylating agentsare those wherein R₁₉ is tert-butyl, isopropyl or isobutyl and RP istert-butyl dimethyl silyl, triisopropyl silyl, tert-butyl diphenyl silylor the like.

The alkylating reagents of formula (5-1) are prepared by reaction of adiol sequentially with a wide variety of compounds for incorporating thecarbonate moiety, followed by a wide variety of compounds forincorporating the silyl moiety. Alkylating reagents include, but are notlimited to, tert-butyl chloroformate, di-tert-butyl dicarbonate, and1-(tert-butoxycarbonyl)imidazole; where as silylating reagents include,but are not limited to tert-butyl dimethyl silyl chloride, tert-butyldimethyl silyl triflate, tert-butyl dimethyl silyl cyanide, andtert-butyl dimethyl silyl imidazole. Both reactions are carried out inthe presence of an organic or an inorganic base as previously describedin scheme l. The temperature of the reactions varies from about −30° C.to about 60° C. Preferably, the alkylating reagent is di-tert-butyldicarbonate and the silylating reagent is tert-butyl dimethyl silylchloride.

The free oxime (5-3) is prepared using essentially the same procedure asfor the deprotection of oxime (1-4) to (3-1) where R₆ is acetyl inscheme 1.

Reduction of oximes of formula (5-3) to the corresponding ketonecompounds of formula (5-4) may be done by, for example, but not limitedto, using a sulfite reducing agent, such as sodium hydrogensulfite,under acidic conditions, typically in protic solvents, as previouslydescribed for the reduction of oximes of formula (3-1) to compounds offormula (3-2). Representative acids include, but are not limited to,acetic acid, formic acid, dilute hydrochloric acid, dilute phosphoricacid, dilute sulfuric acid, and the like. Suitable protic solventsinclude, but are not limited to, mixtures of water and methanol,ethanol, isopropanol, or butanol. The reaction is typically carried outat a temperature from about 50° C. to about 110° C., preferably forabout 1 to about 10 hours.

When the R^(P) ₁ group is R^(P) (i.e., a hydroxy protecting group) in acompound of formula (5-4) then the hydroxy protecting group is removedusing appropriate conditions. For example, when the protecting group isa silyl group, TBAF, hydrofluoric acid or trifluoroacetic acid may beused (see, T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Synthesis 3^(rd) ed., John Wiley & Son, Inc, 1999). Theresulting primary hydroxy group (where R^(P) ₁=H) is converted to thecorresponding tert-butyl carbonate by standard methods known in the art,followed by alkylation of the 11-hydroxy group using a palladium (0)catalyst as previously described in scheme 1, to form compounds offormula (5-6).

Scheme 6 illustrates a procedure for the acylation of the C-3 hydroxygroup of compounds of formula (6-1). The C-3 hydroxy group is acylatedunder basic conditions using a suitable acylating agent to introduce theacyl group of the formula —C(O)—Z—R₂, where Z is O, N, S or —(CH₂)_(t),where t=0 to 4 and R₂ is as previously described, in an aprotic solventas previously described for acylating compounds of formula (3-2).Typical acylating agents include, but are not limited to, acid halides,acid anhydrides, free acids and chloroformates. Typical bases include,but are not limited to, pyridine, DMAP, triethylamine, diisopropylethylamine, N-methyl morpholine, N-methylpyrrolidine, 2, 6-lutidine,1,8-diazabicyclo[5.4.0]undec-7-ene. (See, T. W. Greene and P. G. M. Wutsin Protective Groups in Organic Synthesis 3^(rd) ed., John Wiley & Son,Inc, 1999, and references therein).

Alternately, in compounds of formula (6-1) the C-3 hydroxy group may befurther derivatized to form, for example, ethers, esters, sulfonates,and the like, using methods well known in the art (see, for example, J.March, Advanced Organic Chemistry 4^(th) ed., Wiley & Son, Inc., 1992;and the references therein).

Another method of the present invention, as illustrated in Scheme 7,involves synthesis of the C-3 deoxygenated macrolide (7-2) which can beaccomplished via the two step procedure shown above. In the first step,the xanthate or thiocarbonate of formula 7-1) is formed by the reactionof alcohol of formula (6-1) with the appropriate thiocarbonyl compound.These reactions are typically run in a polar aprotic solvent, preferablytetrahydrofuran, acetonitrile, N,N-dimethylformamide, and the like.Formation of the xanthate can be accomplished, for example, by reactionof the alcohol (6-1) with, for example, but not limited to,carbondisulfide followed by methyliodide, or a dithiocarbonyl imidazoleetc. The thiocarbonate can be prepared by the reaction of the alcoholwith for example, but not limited to, thiocarbonyldimidazole followed bymethanol, ethanol or the like, or a thiochloroformate etc. One skilledin the art will appreciate that other reagents and conditions exist toperform these transformations and that the examples above are forillustrative purposes only and do not limit the scope of this invention.

In the second step, the thiocarbonate or xanthate of formula (7-1) isconverted to compound (7-2). Most typically this is done under radicalconditions using, for example, a silyl hydride such as SiH(TMS)₃,SiH₂Ph₂ or the like, a tin hydride such as BU₃SnH, Ph₃SnH or the like,and a radical initiator such as AIBN or t-butyl peroxide. The preferredsolvent is toluene.

Compounds according to the formula (6-2) may be prepared from compoundsof formula (6-1) by selective hydrogenation methods known in the art,for example, but not limited to, metal hydrides, such as, borane, orhydrogen in the presence of a catalyst, such as, palladium-on-charcoal,platinum metal or oxide, Wilkinson's catalyst and the like (see,Rylander, Hydrogenation Methods; Academic Press: New York, 1985; J.March, Advanced Organic Chemistry 4^(th) ed., Wiley & Son, Inc., 1992;and the references therein).

Compounds (9-1, 9-2 and 9-3, where R is R₃ as previously defined herein)can be prepared by the well-established 1,3-dipolar cycloadditionreactions, such as, but not limited to, reaction of compound (6-1) andan oxime in the presence of NCS in an aprotic solvent such as ethylacetate, methylene chloride, THF, or the like, to form compound (9-1)(see (a) Tufariello, Joseph J. Nitrones in 1,3 [One,Three]-DipolarCycloaddit. Chem. (1984), 2, 83-168. (b) Huisgen, Rolf. 1,3-Dipolarcycloaddition—introduction, survey, mechanism in 1,3 [One,Three]-DipolarCycloaddit. Chem. (1984), 1, 1-176, and the references therein).Compounds (9-2) and (9-3) can be prepared similarly by reacting compound(9-1) with an azide or a nitrone respectively.

Other 1,3-Dipolar cycloaddition reactants useful in formingcycloaddition products with compounds of the present invention such ascompound (6-1) include, but are not limited to, diazoalkane, nitrousoxide, nitrile imine, nitrile ylide, nitrile oxide, etc. (see, Padwa1,3-Dipolar Cycloaddition Chemistry, 2 vols.; Wiley: New York, 1984, andJ. March, Advanced Organic Chemistry, 4^(th) edition; Wiley: New York,1992, and the references therein).

Compound (10-1) is prepared by Diels-Alder reactions, where R_(y) andR_(z) are for example, but not limited to, CHO, COOH, COOR, COR, COAr,CN, NO₂, Ar, CH₂OH, CH₂Cl, CH₂NH₂, CH₂CN, CH₂COOH, halogen, —C═C—, R andthe like, R being R₃ as previously defined herein (see (a) Danishefsky,Samuel. Cycloaddition and cyclocondensation reactions ofhighlyfunctionalized dienes: applications to organic synthesis inChemtracts: Org. Chem. (1989), 2 (5), 273-97, (b) Larock ComprehensiveOrganic Transformation; VCH: New York, 1989, 263-272, and the referencestherein).

Aziridines such as compound (10-2) can be obtained from, for example,but not limited to, the reaction of compound (6-1) with iodine in thepresence of a primary amine in an aprotic solvent such as methylenechloride, THF, and the like.

Lactones such as compound (10-3) can be obtained by a variety ofreactions such as but not limited to, reaction with: manganese (III)acetate in the presence of acetic acid, lead tetraacetate,α-bromocarboxylic acids in the presence of benzoyl peroxide etc. (see,Larock Comprehensive Organic Transformation; VCH: New York, 1989; J.March, Advanced Organic Chemistry, 4^(th) edition; Wiley: New York,1992, and the references therein).

Compound (11-1) is prepared by osmium tetraoxide (OsO₄) catalyzeddihydroxylation of the double bond. In a typical procedure, compound(6-1) is treated with about 1 to about 3 equivalents of NMO in a solventlike t-butanol or acetone, with or without water, in the presence ofabout 1 to about 10% of OSO₄. Compound (11-2) can then be obtained fromcompound (11-3) through standard acylation or alkylation of the diol,where R₇ and R₈ are independently selected from R₃ and where R₃ is aspreviously defined herein.

Compound (11-3) is prepared by epoxidation of the double bond withreagents such as, but not limited to, peracids, e.g. m-CPBA, hydrogenperoxide, t-BuOOH etc. (see (a) Chem. Rev. 1989, 89, 431; (b) Chem. Rev.1992, 92, 873, and references therein).

Compounds of formula (12-1) can be converted to compounds of formula(12-2) by, for example, but not limited to, hydroboration with a boranereagent, for example, B₂H₆-TBF, 9-BBN (9-borabicyclo[3.3.1]nonane), andthe like, (optionally complexed with ThF, dimethylsulfide, phosphines,tertiary amines and the like) and followed by treatment with hydrogenperoxide and NaOH.

Compounds of formula (12-2) may be oxidized to compounds of formula(12-3) with a suitable oxidizing agent. Compounds of formula (12-3) canbe reacted with appropriate substituted hydroxylamines of the generalformula RONH₂ where R is preferably R₃, where R₃ is as previouslydefined, in a protic solvent under acidic or basic conditions to givecompounds of the formula (12-4). Representative acids include, but arenot limited to, hydrochloric acid, phosphoric acid, sulfuric acid,p-toluenesulfonic acid, etc. Representative bases include, for example,triethylamine, pyridine, diisopropylethyl amine, 1,5-lutidine, and thelike. Appropriate solvents include, but are not limited to, methanol,ethanol, water, tetrahydrofuran, 1,2-dimethoxyethane and ethyl acetate.

Also, compounds of the formula (12-3), where the ketone is on the 6,11-4-carbon bridge, may be further derivatized, for example, but notlimited to, conversion to the corresponding amines by reductiveamination, reaction with hydrazines to form the correspondinghydrazones, conversion to substituted alkenes by Wittig reaction,alkylation with Grignard reagent etc., by standard methods known in theart and from references incorporated herein.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art, and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1

Compound of Formula (II): A=B=H; X and Y Taken Together With the CarbonAtom Which They are Attached to=C═N—OH; R_(x)=H and R₄″=C(O)C₆H₅.

Step 1a: Compound of Formula (XVI): R₆=C(O)C₆H₅, R_(x)=C(O)C₆H₅ andR₄″=C(O)C₆H₅;

A solution of erythromycin A oxime (27.5 g, 36.7 mmol), benzoicanhydride (34.9 g, 154 mmol) in 200 ml THF was added to triethylamine(22.5 ml, 161.6 mmol) and DMAP (4.49 g, 36.7 mmol) at room temperatureand stirred for 24 hrs. The reaction mixture was condensed to 100 ml.Then 300 ml of ethyl acetate was added and washed with sat. NaHCO₃ (300ml×3) and brine (300 ml×1). The organic phase was dried on anhydroussodium sulfate and the solvent was removed in vacuo. To this secondresidue was added hexane (100 ml) and the solvent was removed in vacuo.This procedure (addition of hexane and concentration in vacuo) wasrepeated 3 times. The resulting white foam residue was dried in vacuo toafford the title compound (˜90 g).

MS (ESI) m/z=1061 (M+H)⁺.

Step 1b: Compound of Formula (II): A=B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—O—C(O)C₆H₅, R_(x)=C(O)C₆H₅ andR₄″=C(O)C₆H₅.

A mixture of the compound from step 1a (21.9 g, 25 mmol),2-methylene-1,3-propane-[bis-(tert-butyl)carbonate] (18.02 g, 62.25mmol) and 1,4-bis(diphenylphosphino)-butane (640 mg, 1.5 mmol) wasdissolved in freshly distilled THF (250 ml). To the solution was addedPd₂(dba)₃ (687 mg, 0.75 mmol). The reaction mixture was heated to refluxslowly. After refluxing for 14 hours, the reaction was cooled to roomtemperature, diluted with 400 ml ethyl acetate, and washed withsaturated NaHCO₃ (400 ml) and brine (400 ml). The organic phase wasdried over Na₂SO₄, the solvent was removed in vacuo and the solidresidue was purified by silica gel chromatography (acetone: hexane/1:2)to give the title compound (22 g).

MS (ESI) m/z=1113 (M+H)⁺.

Step 1c: Compound of Formula (II): A=B=H: X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—OH; R_(x)=H and R₄″=C(O)C₆H₅.

A solution of the compound from Step 1b (22 g) in 400 ml methanol wasrefluxed for 48 hours. The solvent was removed in vacuo and the compoundwas purified by column chromatography (CH₂Cl₂: 2M ammonia in MeOH/95:5)to give the title compound (18.5 g).

MS (ESI) m/z=905 (M+H)⁺.

Example 2

Compound of Formula (IV): A=3-quinolyl; B=H; X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—OH; R_(x)=H and R₄″=C(O)CH₃.

Step 2a: Compound of Formula (XVI): R₆=C(O)CH₃, R_(x)=C(O)CH₃ andR₄″=C(O)CH₃.

Erythromycin A oxime was treated with acetic anhydride following thesame procedure described in step 1a to give the title compound.

Step 2b: Compound of Formula (II): A=B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C(O)CH₃, R_(x)=C(O)CH₃ andR_”=C(O)CH₃.

The compound from step 1a (0.54 g, 0.60 mmol) in 20 mL anhydrous THFwith Pd₂(dba)₃ (46 mg, 0.05 mmol) and dppb (46 mg, 0.05 mmol) wasdegassed at −78° C. Then2-methylene-1,3-propane-[bis-(tert-butyl)carbonate] (0.50 g, 1.8 mmol)was introduced quickly under nitrogen. The reaction solution was heatedto reflux slowly and kept refluxing for 12 hours. The reaction wascooled and solvent was removed under vacuum. The residue was purified bychromatography on a silica gel column (eluting with acetone:hexanes/1:1)to provide the title compound (0.4 g, 70%). MS (ESI) m/z=927 (M+H)⁺.

Step 2c: Compound of Formula (IV): A=3-quinolyl, B=H, X and Y TakenTogether With the Carbon Atom They are Attached to=C(O)CH₃,R_(x)=C(O)CH₃ and R_(x)=C(O)CH₃.

The compound from step 2b (0.46 g, 0.50 mmol), 3-bromoquinoline (0.21 g,1.0 mmol), Pd(OAc)₂ (15 mg, 0.07 mmol), (o-Tolyl)₃P (50 mg, 0.16 mmol)and triethyl amine (0.5 mL, 4.0 mmol) were dissolved in 10 mL CH₃CN andthe solution was degassed at −40° C. The reaction mixture was warmed upto room temperature and sealed under nitrogen, then was heated at 50° C.for 1.5 hours, then left at 78° C. for 12 hours. Then the reactionmixture was diluted with ethyl acetate, washed with saturated aqueousNaHCO₃, and dried over anhydrous Na₂SO₄. The solvent was evaporated andthe residue was purified by chromatography on a silica gel column(eluting with acetone:hexanes/2:3) to provide the title compound (0.17g, 33%).

MS (ESI) m/z=1054 (M+H)⁺.

Step 2d: Compound of Formula (IV): A=3-quinolyl. B=H: X and Y takentogether with the carbon atom they are attached to=C═N—OH; R_(x)=H andR₄″=C(O)CH₃.

A solution of the compound from Step 2c in methanol (10 mL) was heatedat 65° C. for 48 hours. The solvent was evaporated under vacuum.Purification on silica gel column (eluting with CH₂Cl₂ containing 5% 2Mammonia solution in methanol) gave the title compound (0.14 g, 90%) as awhite solid.

MS (ESI) m/z=970 (M+H)⁺.

Selected ¹³C-NMR (100 MHz, CDCl₃): δ 170.8, 164.6, 152.2, 151.0, 146.8,135.8, 134.0, 128.7, 128.3, 128.2, 127.5, 126.4, 112.8, 102.7, 97.5,82.1, 81.0, 79.6, 79.1, 78.9, 77.8, 77.5, 75.9, 73.2, 71.2, 68.5, 65.5,63.3, 60.6, 53.6, 49.9, 45.9, 44.5, 41.7, 40.4.

Example 3

Compound of Formula (II): A=C(O)OCH₃; B=H: X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—OH; R_(x)=H and R₄″=C(O)C₆H₅.

Step 3a: Compound of Formula (II): A=C(O)OCH₃, B=H, X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—O—C(O)C₆H₅,R_(x)=C(O)C₆H₅ and R₄″=C(O)C₆H₅.

A mixture of the compound from step 1a (1.3 mmole),tBuOC(O)OCH₂C(CO₂Me)═CHCH₂OC(O)OtBu and1,4-bis(diphenylphosphino)-butane (0.04 mmole) are dissolved in freshlydistilled THF. To the solution is added Pd₂(dba)₃ (0.02 mmole). Thereaction mixture is heated to reflux slowly. After refluxing for 14hours, the reaction is cooled to room temperature, diluted with ethylacetate, and washed with saturated NaHCO₃ and brine. The organic phaseis dried over Na₂SO₄, the solvent is removed in vacuo and the solidresidue is purified by silica gel chromatography (acetone: hexane/1:2)to give the title compound.

Step 3b: Compound of Formula (II): A=C(O)OCH; B=H; X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—OH; R_(x)=H andR₄″=C(O)C₆H₅.

The compound from Step 3a is refluxed in methanol for 12 hours. Thesolvent is evaporated and the residue is purified by silica gelchromatography (5-10% 2M NH₃ in methanol in CH₂Cl₂) to give the titlecompound.

Example 4

Compound of Formula (II): A=C(O)—OH; B=H; X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—OH; R_(x)=H and R₄″=H.

To a solution of the compound from Example 3 (10 mg, 0.01 mmol) in TBF(1 mL) and distilled water (1 mL) is added iN LiOH (0.1 mL, 0.10 mmol).The mixture is stirred for 5-10 hours at 50° C. Then water (10 mL) isadded and the mixture extracted with ethyl acetate. The combined organiclayer is dried over anhydrous Na₂SO₄. The solvent is concentrated undervacuum and the residue is purified on a silica gel column to provide thetitle compound.

Example 5

Compound of Compound of Formula (II): A=B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═O, R_(x)=H and R₄″=COCH₃.

Step 5a: Compound: HO—CH₂—CH═CH—CH2—OSi(CH₃)₂(C(CH₃)₃.

A suspension of NaH (1.26 g, 50 mmol) in 40 ml of THF was added to asolution of diol (4.4 g, 50 mmol) in 30 ml of THF. The mixture wasstirred at room temperature for 45 minutes and was added with a solutionof tert-butyldimethylsilyl chloride (7.54 g, 50 mmol) in 30 ml of TBF.The mixture was stirred at room temperature for 1 hour and quenched withsaturated NaHCO₃ (200 ml), then extracted with ether (150 ml×2), and thecombined organic layers were dried over MgSO₄. The solvent was removedand the resulting oil was purified on silica chromatography(Hexane:ethyl acetate/10:1) to give the title compound (8.4 g).

Step 5b: Compound: (CH₃)₃C—O—C(O)—O—CH₂—CH═CH—CH₂—OSi(CH₃)₂(C(CH₃)₃).

A solution of compound from Step 5a (8.1 g, 40 mmol) in 100 ml ofmethylenechloride was added to Boc₂O (13.1 g, 60 mmol),tetrabutylammoniumhydrogensulfate (1.2 g, 3.5 mmol) and 30 ml of 6NNaOH. The reaction mixture was stirred at room temperature for 16 hours,then diluted with 100 ml of methylene chloride and washed with saturatedNaHCO₃ (200 ml×3). The organic layer was dried over Na₂SO₄. The solventwas removed and the residue was purified on silica gel chromatography(Hexane:ethylacetate/96:4) to give the title compound (6.8 g).

Step 5c: Compound of Formula (XVII): A=B=H, V taken together with thecarbon atom it is attached to=C═N—O—C(O)CH₃, R_(x)=C(O)CH₃, R^(P)₁=−Si(CHi)₂(C(CH₃)₃) and R₄″=C(O)CH₃.

The compound from Step 5b,tert-Butyl-OC(O)—OCH₂CH═CHCH₂—O-tert-butyldimethylsilyl (0.9 g, 3 mmol),1,4-bis(diphenylphosphino)butane (170 mg, 0.4 mmol) and Pd₂(dba)₃ (183mg, 0.2 mmol) were added into a solution of ery-9-oxime triacetate (1.75g, 2 mmol) in tetrahydrofuran (10 ml) at room temperature. The reactionmixture was refluxed under nitrogen overnight, cooled to roomtemperature and the solvent was removed in vacuo. The residue waspurified by silica gel chromatography (acetone:hexanes/1:3) to give thetitle compound (1.5 g).

MS (ESI) m/z=1059 (M+H).

Step 5d: Compound of Formula (XVII): A=B=H, V Taken Together With theCarbon Atom it is Attached to=C═N—OH, R_(x)=H, R^(P)₁=—Si(CH₃)₂(C(CH₃)₃) and R₄″=C(O)CH₃.

A solution of the compound from Step 5c (3.18 g, 3 mmol) in methanol (80ml) was refluxed for 8 hours. The reaction was cooled to roomtemperature, the solvent was removed in vacuo and the residue waspurified by silica gel chromatography (2M ammonia in methanol:dichloromethane/3:97) to give the title compound (2.6 g).

MS (ESI) m/z=975 (M+H).

Step 5e: Compound of Formula (XVII): A=B=H, V Taken Together With theCarbon Atom it is Attached to=C═OH, R_(x)=R^(p) ₁=H and R₄″=C(O)CH₃.

Formic acid (0.38 ml, 10 mmol) and Na₂S₂O₄ (1.39, 8 mmol) was added intoan emulsion of the compound from Step 5d (2.44 g, 2.5 mmol) inisopropanol (25 ml) and water (30 ml). The mixture was heated to 90° C.and stirred at that temperature for 8 hours. The reaction mixture wascooled to room temperature, diluted with ethyl acetate (60 ml), washedwith saturated sodium bicarbonate (3×60 ml), and dried over sodiumsulfate. The solvent was removed in vacuo and the residue was purifiedby silica gel chromatography (2M ammonia inmethanol:dichloromethane/3:97) to give the title compound (1.7 g).

MS (ESI) m/z=846 (M+H).

Step 5f: Compound of Formula (XVII): A=B=H, V Taken Together With theCarbon Atom it is Attached to=C═O, R_(x)=C(O)CH₃, R^(p) ₁=H andR₄″=C(O)CH₃.

Acetic anhydride (94 μl, 1 mmol) was added into a solution of thecompound from Step 5e (338.4 mg, 0.4 mmol) in dichloromethane (5 ml).The mixture was stirred at room temperature for 16 hours. The solventwas removed in vacuo and the residue was purified by silica gelchromatography (acetone:hexane/4:6) to give the title compound (330 mg).

MS (ESI) m/z=888 (M+H).

Step 5g: Compound of Formula (XVII): A=B=H, V Taken Together With theCarbon Atom it is Attached to=C═O, R_(x)=C(O)CH₃, R^(p) ₁=C(O)—O—C(CH₃)₃and R₄″=C(O)CH₃.

Di-tert-butyl-dicarbonate (69 μl, 0.3 mmol) was added to a solution ofthe compound of Step 5f (178 mg, 0.2 mmol) and triethylamine (56 μl, 0.4mmol) in dichloromethane (8 ml) at room temperature. After 10 minutes,N,N-dimethylamino pyridine (12.2 mg, 0.1 mmol) was added. The resultingsolution was stirred at room temperature for 2 hours. The solvent wasremoved in vacuo and the residue was purified by silica gelchromatography (acetone:hexane/1:3) to give the title compound (180 mg).

MS (ESI) m/z=988 (M+H).

Step 5h: Compound of Formula (II): A=B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═O, R_(x)=C(O)CH₃ and R₄″=C(O)CH₃.

1,4-Bis(diphenylphosphino)butane (8.5 mg, 0.02 mmol) and Pd₂(dba)₃ (9.2mg, 0.01 mmol) is added to a solution of the compound of Step 5g (98.8mg, 0.1 mmol) in 2 ml anhydrous THF at room temperature. The resultingmixture is refluxed for 30 minutes. The solvent is removed in vacuo andthe residue is used for next step reaction without purification.

Step 5i: Compound of Formula (II): A=B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═O, R_(x)=H and R₄″=C(O)CH₃.

The compound from Step 5h is stirred in methanol for 24 hours. Removalof the solvent gives the title compound.

Example 6

Compound of Formula (II): A=B=H; X and Y Taken Together With the CarbonAtom They are Attached to=C═N—C(O)CH₃; R_(x)″=H and R₄″=C(O)C₆H₅.

Step 6a: Compound of Formula (II): A=B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═NH, R_(x)=H and R₄″=C(O)C₆H₅.

The compound from Step 1c in methanol is treated with titaniumtrichloride (20% in 3% hydrochloric acid) following the proceduredescribed in Step 1d, except the reaction is quenched with aqueoussodium bicarbonate after 2-3 hours. The aqueous solution is extractedwith methylene chloride 4 times and the organic phase is combined anddried over sodium sulfate. The solvent is then removed under vacuum andthe crude residue is purified by chromatography on a silica gel columnto provide the title compound.

Step 6b: Compound of Formula (II): A=B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃, R_(x)=C(O)CH₃ andR₄″=C(O)C₆H₅.

The compound from Step 6a is treated with 2.5 equivalents of aceticanhydride and triethylamine in dichloromethane. The reaction mixture isstirred at room temperature for 3 hours, then diluted withdichloromethane and washed with saturated sodium bicarbonate and brine.The organic phase is dried over sodium sulfate and the solvent isremoved in vacuo. The residue is purified by silica gel chromatography(hexanes:acetone/1:1) to give the title compound.

Step 6c: Compound of Formula (II): A=B=H; X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=H andR₄″=C(O)C₆H₅.

The compound from Step 6b is stirred in methanol for 24 hours. Removalof the solvent gives the title compound.

Example 7

Compound of Formula (VIII): Q=—C(C₆H₅)═N—O—: X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃: R_(x)=H andR₄″=C(O)C₆H₅.

Step 7a: Compound of Formula (VIII): Q=—C(C₆H₅)═N—O—, X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—C(O)CH₃,R_(x)=C(O)CH₃ and R₄″=C(O)C₆H₅.

To a solution of benzaldoxime (1.2 mmol) in 5 mL ethyl acetate is addedNCS (0.17 g, 1.2 mmol) and NaHCO₃ (0.25 g, 2.5 mmol) and 1 drop ofwater. The compound from Step 6b (1.0 mmol) is added to the reactionmixture and stirred at room temperature for 12 hours. Then the reactionmixture is diluted with ethyl acetate, washed with saturated aqueousNaHCO₃, and dried over anhydrous Na₂SO₄. The solvent is evaporated andthe residue is purified on silica gel column to give the title compound.

Step 7b Compound of Formula (VIII): Q=—C(C₆H₅)═N—O—; X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=Hand R₄″=C(O)C₆H₅.

The compound from Step 7a is stirred in methanol for 24 hours. Removalof the solvent gives the title compound.

Example 8

Compound of Formula (VIII): Q=—O—C(O)—O—; X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=H andR₄″=C(O)C₆H₅.

Step 8a: Compound of Formula (X): E=G=—OH, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=C(O)CH₃ andR₄″=C(O)C₆H₅.

To a solution of the compound from Step 6b (1.0 mmol) and NMO (1.2 mmol)in 5 mL t-butanol is added 4% OSO₄ (catalytic amount). The reactionmixture is stirred for 3 hours at room temperature. The solvent is thenremoved under vacuum and the crude residue is purified by chromatographyon a silica gel column to provide the title compound.

Step 8b: Compound of Formula (VIII): Q=—O—C(O)—O—, X and Y takentogether with the carbon atom they are attached to=C═N—C(O)CH₃,R_(x)=C(O)CH₃ and R₄″=C(O)C₆H₅.

The compound from Step 8a (1.0 mmol), CDI (1.2 mmol) and 0.2 mLtriethylamine are dissolved in 15 mL methylene chloride. The reactionmixture is stirred for 12 hours at room temperature. The reaction isquenched with NaHCO₃ aqueous solution and extracted with methylenechloride. The combined organic layers are dried over anhydrous Na₂SO₄.The solvent is evaporated and the residue is purified by chromatographyon a silica gel column to provide the title compound.

Step 8c: Compound of Formula (VIII): Q=—O—C(O)—O—; X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=Hand R₄″=C(O)C₆H₅.

The compound from Step 8b is stirred in methanol for 24 hours. Removalof the solvent gives the title compound.

Example 9

Compound of Formula (VIII): Q=—O—; X and Y Taken Together With theCarbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=H and R₄″=C(O)C₆H₅.

Step 9a: Compound of Formula (VIII): Q=—O—; X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=C(O)CH₃ andR₄″=C(O)C₆H₅.

To a solution of the compound from Step 6b (1.0 mmol) in CH₂C₁₂ is addedm-CPBA (1.2 mmol). The reaction mixture is stirred for 3 hours at roomtemperature. The solvent is then removed under vacuum and the cruderesidue is purified by chromatography on a silica gel column to providethe title compound.

Step 9b: Compound of Formula (VIII): Q=—O—; X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=H andR₄″=C(O)C₆H₅.

The compound from Step 9a is stirred in methanol for 24 hours. Removalof the solvent gives the title compound.

Example 10

Compound of Formula (VIII): Q=—O—; X and Y Taken Together With theCarbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=H and R₄″=H.

To a solution of the compound from Example 9 (10 mg, 0.01 mmol) in THF(1 mL) and distilled water (1 mL) is added 1N LiOH (0.1 mL, 0.10 mmol).The mixture is stirred for 5-10 hours at 50° C. Then water (10 mL) isadded and extracted with ethyl acetate. The combined organic layer isdried over anhydrous Na₂SO₄. The solvent is concentrated under vacuumand the residue is purified on a silica gel column to provide the titlecompound.

Example 11

Compound of Formula (II): A=B=H; X and Y Taken Together With the CarbonAtom They are Attached to=C═NC(O)CH₂OCH₃; R_(x)=H and R₄″=C(O)C₆H₅.

Step 11a: Compound of Formula (II): A=B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═NC(O)CH₂OCH₃, R_(x)=C(O)CH₂OCH₃and R₄″C(O)C₆H₅.

To a solution of methoxyacetic acid (2.5 mmol) in CH₂Cl₂ is added DCC(2.5 mmol) at 0° C. The mixture is stirred for 10 minutes. The compoundfrom Step 6a (1.0 mmol) in CH₂Cl₂ is added and the solution is stirredfor 12 hours. The solvent is removed under vacuum and the residue ispurified on a silica gel column to provide the title compound.

Step 11b: Compound of Formula (I): A=B=H; X and Y Taken Together Withthe Carbon Atom They are Attached to=C═NC(O)CH₂OCH₃; R_(x)=H andR₄″=C(O)C₆H₅.

The compound from Step 11a is stirred in methanol for 24 hours. Removalof the solvent gives the title compound.

Example 12

Compound of Formula (II): A=B=H; X and Y Taken Together With the CarbonAtom They are Attached to=C═N—C(O)—CH₂OCH₃; R_(x)=H and R₄″=H.

To a solution of the compound from Example 11 (10 mg, 0.01 mmol) in THF(1 mL) and distilled water (1 mL) is added 1N LiOH (0.1 mL, 0.10 mmol).The mixture is stirred for 5-10 hours at 50° C. Then water (10 Ml) isadded and extracted with ethyl acetate. The combined organic layer isdried over anhydrous Na₂SO₄. The solvent is concentrated under vacuumand the residue is purified on a silica gel column to provide the titlecompound.

Example 13

Compound of Formula (IV): A=3-quinolyl; B=H, X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=H andR₄″=C(O)C₆H₅;

Step 13a: Compound of Formula (IV): A=3-quinolyl, B=H, X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—C(O)CH₃,R_(x)=C(O)CH₃ and R₄″=C(O)C₆H₅;

The compound from Step 6b (0.50 mmol), 3-bromoquinoline (0.21 g, 1.0mmol), Pd(OAc)₂ (15 mg, 0.07 mmol), (o-Tolyl)₃P (50 mg, 0.16 mmol) andtriethyl amine (0.5 mL, 4.0 mmol) are dissolved in 10 mL CH₃CN and thesolution is degassed at −40° C. The reaction mixture is warmed up toroom temperature and sealed under nitrogen, then is heated at 50° C. for1.5 hours, then left at 78° C. for 12 hours. Then the reaction mixtureis diluted with ethyl acetate, washed with saturated aqueous NaHCO₃, anddried over anhydrous Na₂SO₄. The solvent is evaporated and the residueis purified by chromatography on a silica gel column to provide thetitle compound.

Step 13b: Compound of Formula (IV): A=3-quinolyl; B=H; X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=Hand R₄″=C(O)C₆H₅.

The compound from Step 13a is stirred in methanol for 24 hours. Removalof the solvent gives the title compound.

Example 14

Compound of Formula (IV): A=3-quinolyl; B=H; X and Y Taken Together Withthe Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=H and R₄″=H.

To a solution of the compound from Example 13 (10 mg, 0.01 mmol) in T1F(1 mL) and distilled water (1 mL) is added 1N LiOH (0.1 mL, 0.10 mmol).The mixture is stirred for 5-10 hours at 50° C. Then water (10 mL) isadded and extracted with ethyl acetate. The combined organic layer isdried over anhydrous Na₂SO₄. The solvent is concentrated under vacuumand the residue is purified on a silica gel column to provide the titlecompound.

Example 15

Compound of Formula (II): A=C(CH═CH—C₆H₅); B=H; X and Y Taken TogetherWith the Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=H andR₄″=C(O)C₆H₅.

Step 15a: Compound of Formula (II): A=C(CH═CH—C₆H₅), B=H, X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—C(O)CH₃,R_(x)=C(O)CH₃ and R₄″=C(O)C₆H₅.

The compound from Step 6b (1.0 equiv.) is dissolved in anhydrous DMF.β-bromostyrene (3.0 equiv.) and K₂CO₃ (4 equiv.) are added at roomtemperature. The mixture is degassed briefly and a catalytic amount ofdihydrogen dichlorobis(di-tert-butylphosphinito-κP)palladate(2-) (POPdfrom Combiphos catalysts, Inc.) is added. The reaction mixture is heatedto 100° C. in a sealed tube for 48 hours. Ethyl acetate is added and thesolution is washed 3 times with NaHCO₃ aqueous solution. The organiclayer is dried over anhydrous Na₂SO₄. The solvent is evaporated undervacuum and the residue is purified by chromatography on a silica gelcolumn to provide the title compound.

Step 15b: Compound of Formula (II): A=C(CH═CH—C₆ H₅); B=H; X and Y TakenTogether With the Carbon Atom They are Attached to=C═N—C(O)CH₃; R_(x)=Hand R₄″=C(O)C₆H₅.

The compound from Step 15a is stirred in methanol for 24 hours. Removalof the solvent gives the title compound.

Example 16

Compound of Formula (II): A=C(CH═CH—C₆H₅); B=H; X and Y Taken TogetherWith the Carbon Atom They are Attached to=C═NC(O)CH₃; R_(x)=H and R₄″=H.

To a solution of the compound from eExample 15 (10 mg, 0.01 mmol) in THF(1 mL) and distilled water (1 mL) is added 1N LiOH (0.1 mL, 0.10 mmol).The mixture is stirred for 5-10 hours at 50° C. Then water (10 mL) isadded and extracted with ethyl acetate. The combined organic layer isdried over anhydrous Na₂SO₄. The solvent is concentrated under vacuumand the residue is purified on a silica gel column to provide the titlecompound.

Example 17

Compound of Formula (II): A=H; B=H; X and Y Taken Together With theCarbon Atom They are Attached to=C═NC(O)CH₃; R_(x)=H and R₄″=H.

To a solution of the compound from Step 6c (10 mg, 0.01 mmol) in THF (1mL) and distilled water (1 mL) is added 1N LiOH (0.1 mL, 0.10 mmol). Themixture is stirred for 5-10 hours at 50° C. Then water (10 mL) is addedand extracted with ethyl acetate. The combined organic layer is driedover anhydrous Na₂SO₄. The solvent is concentrated under vacuum and theresidue is purified on a silica gel column to provide the titlecompound.

Although the invention has been described in detail with respect tovarious preferred embodiments it is not intended to be limited thereto,but rather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

1. A compound represented by the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof whereinW is selected from the group consisting of: (a) —CH₂—C(A)═C(B)—CH₂—; wherein, A and B are independently selected from the group consistingof: (i) hydrogen; (ii) deuterium; (iii) halogen; (iv) R₁, wherein R₁ isselected from the group consisting of: a. C₁-C₆ alkyl, optionallysubstituted with one or more substituents selected from the groupconsisting of: halogen, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; b. C₂-C₆ alkenyl, optionally substituted withone or more substituents selected from the group consisting of: halogen,aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and c.C₂-C₆ alkynyl, optionally substituted with one or more substituentsselected from the group consisting of: halogen, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; (v) R₂, wherein R₂ is selectedfrom the group consisting of: a. aryl; b. heteroaryl; c. substitutedaryl; and d. substituted heteroaryl; (vi)—(C₁-C₃-alkyl)-M-(C₁-C₃-alkyl)-R₂, wherein M=—O—, —NH—, —N(CH₃)—,—NHC(O)— or —S(O)_(n)—, wherein n=0, 1 or 2, and R₂ is as previouslydefined; (vii) —(C₁-C₃-alkyl)-M-R₂, wherein M and R₂ are as previouslydefined; (viii) —C(O)-J-R₃, wherein J is absent, O or S, and R₃ is H, R₁or R₂;  where R₁ and R₂ are as previously defined; and (ix)—C(O)—NR₁₁R₁₂, wherein R₁₁ and R₁₂ are each independently selected fromthe group consisting of: a. hydrogen; b. C₁-C₆-alkyl, optionallysubstituted with one or more substituents selected from the groupconsisting of: halogen, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; c. C₂-C₆-alkenyl, optionally substituted withone or more substituents selected from the group consisting of: halogen,aryl, substituted aryl, heteroaryl, and substituted heteroaryl; d.C₂-C₆-alkynyl, optionally substituted with one or more substituentsselected from the group consisting of: halogen, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; and e. R₁ and R₁₂ taken togetherwith the nitrogen atom to which they are connected form a 3- to7-membered ring which may optionally contain one or more heterofunctionsselected from the group consisting of: —O—, —NH—, —N(C₁-C₆-alkyl)-,—N(R₂)—, —S(O)_(n)—, wherein n and R₂ are as previously defined; (b)—CH₂—CH(A)-C(B)=CH—, wherein A and B are as previously defined; (c)—CH₂—CH(E)-CH(G)-CH₂—; wherein E and G are independently selected fromthe group consisting of: (i) A, wherein A is as previously defined; (ii)—OH; (iii) —O—R₉, wherein R^(P) is a hydroxy protecting group; (iv)—O—R₉, wherein R₉ is R₁ or R₂, and wherein R₁ and R₂ are as previouslydefined; (v) —S(O)_(n)R₉, wherein n and R₉ are as previously defined;(vi) —NHC(O)R₃, wherein R₃ is as previously defined; (vii)—NHC(O)NR₁₁R₃, wherein R₁₁ and R₃ are as previously defined; (viii)—NHS(O)₂R₉, wherein R₉ is as previously defined; (ix) —NHR₁₃, whereinR₁₃ is an amino protecting group; and (x) —NR₁₁R₁₂, wherein R₁₁ and R₁₂are as previously defined; (d)

 wherein: (i) -Q- is selected from the group consisting of: —O—;—O—C(O)—CH(R₇)—; —N(R₇)—; —O—C(O)—N(R₇)—; —O—C(O)—O—; —N(R₇)—N═N—;—C(R₇)═N—O—; and —CH(R₇)—N(R₈)—O—; wherein R₇ and R₉ are independentlyselected from R₃, wherein R₃ is as previously defined; or (ii) -Q- takentogether with the two carbon atoms it is attached to is selected fromthe group consisting of: a. cycloalkylene; b. cycloalkenylene; and c.heterocycloalkylene; and (e) —CH₂—C(R4)(R₅)—CH₂—CH₂—; wherein R₄ and R₅taken together with the carbon atom to which they are attached areselected from the group consisting of: (i) C═O; (ii) C(OR₁)₂, wherein R₁is as previously defined; (iii) C(SR₁)₂, wherein R₁ is as previouslydefined; (iv) C[—O(CH₂)_(m)]₂, wherein m is 2 or 3; (v) C[—S(CH₂)_(m)]₂,wherein m is as previously defined, (vi) C═CHR₃, wherein R₃ is aspreviously defined; (vii) C═N—O—R₃, wherein R₃ is as previously defined;(viii) C═NNHR₃, wherein R₃ is as previously defined; (ix) C═NNHC(O)R₃,wherein R₃ is as previously defined; (x) C═NNHC(O)NR₁₁R₃, wherein R₁₁and R₃ are as previously defined; (xi) C═NNHS(O)₂R₉, wherein R₉ is aspreviously defined; (xii) C═NNHR₁₃, wherein R₁₃ is as previouslydefined; and (xiii) C═NR₉, wherein R₉ is as previously defined; X and Yare: (a) independently selected from the group consisting of: (i)hydrogen; (ii) deuterium; (iii) —OH; (iv) —OR^(P), wherein R^(P) is aspreviously defined; and (v) —NR₁₄R₁₅, wherein R₁₄ and R₁₅ are eachindependently selected from the group consisting of: a. hydrogen; b.C₁-C₁₂ alkyl, optionally substituted with one or more substituentsselected from the group consisting of halogen, aryl, substituted aryl,heteroaryl and substituted heteroaryl; and c. R₁₄ and R₁₅, takentogether with the nitrogen atom to which they are attached form a 3 to10 membered heterocycloalkyl ring optionally substituted with one ormore hetero atoms selected from the group consisting of O, S and N; or(b) taken together with the carbon atom to which they are attached areselected from the group consisting of: (i) C═O; (ii) C═NR₃, wherein R₃is as previously defined; (iii) C═NC(O)R₃, wherein R₃ is as previouslydefined; (iv)C═N—OR₆, wherein R₆ is selected from the group consistingof: a. hydrogen; b. —CH₂O(CH₂)₂OCH₃; c. —CH₂O(CH₂O)_(n)CH₃, wherein n isas previously defined; d. C₁-C₁₂ alkyl, optionally substituted with oneor more substituents selected from the group consisting of halogen,aryl, substituted aryl, heteroaryl and substituted heteroaryl; e. C₃-C₁₂cycloalkyl; f. C(O)—C₁-C₁₂ alkyl; g. C(O)—(C₃-C₁₂ cycloalkyl); h.C(O)—R₂, wherein R₂ is as previously defined; and i.—Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and R_(c) are eachindependently selected from the group consisting of C₁-C₁₂ alkyl, aryland substituted aryl; and (v) C═N—O—C(R₁₆)(R₁₇)—O—R₁₈, wherein R₁₆ andR₁₇ taken together with the carbon atom to which they are attached forma C₃ to C₁₂ cycloalkyl group or each independently is selected from thegroup consisting of: hydrogen, and C₁-C₁₂ alkyl; and R₁₈ is selectedfrom the group consisting of: a. hydrogen; b. —CH₂O(CH₂)₂OCH₃; c.—CH₂O(CH₂O)_(n)CH₃, wherein n is as previously defined; d. C₁-C₁₂ alkyl,optionally substituted with one or more substituents selected from thegroup consisting of halogen, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; e. C₃-C₁₂ cycloalkyl; and f.—Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and R_(c) are aspreviously defined; L is selected from the group consisting of: (a)—CH(OH)CH₃; (b) C₁-C₆ alkyl, optionally substituted with one or moresubstituents selected from the group consisting of aryl, substitutedaryl, heteroaryl, and substituted heteroaryl; (c) C₂-C₆ alkenyl,optionally substituted with one or more substituents selected from thegroup consisting of aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; and (d) C₂-C₆ alkynyl, optionally substituted with one ormore substituents selected from the group consisting of aryl,substituted aryl, heteroaryl, and substituted heteroaryl; K is selectedfrom the group consisting of: (a) R₁₀, wherein R₁₀ is selected from thegroup consisting of: (i) hydrogen; (ii) —OR^(P), wherein R^(P) is aspreviously defined; (iii) —OR₃, wherein R₃ is as previously defined;(iv) —OC(O)R₃, wherein R₃ is as previously defined; (v) —OC(O)NR₁₁R₃,wherein R₁₁ and R₃ are as previously defined; and (vi) —S(O)_(n)R₉,wherein n and R₉ are as previously defined; and (b)

 wherein R₃″ is hydrogen or methyl; R₄″ is hydrogen or R^(P), whereinR^(P) is as previously defined; and R_(x) is hydrogen or R^(P), whereinR^(P) is as previously defined.
 2. A compound according to claim 1wherein X and Y taken together with the carbon atom to which they areattached are selected from the group consisting of: C═O, C═NR₃,C═N—O—R₆, C═N—C(O)R₃ and C═N—O—C(R₁₆)(R₁₇)—O—R₁₈, wherein R₃, R₆, R₁₆,R₁₇ and R₁₈ are as defined in claim
 1. 3. A compound according to claim2 wherein X and Y taken together with the carbon atom to which they areattached are selected from the group consisting of: C═NC(O)CH₃ andC═N—O—CH₂—O—CH₃.
 4. A compound according to claim 1 represented by theformula:

wherein A, B, X, Y, Rx and R₄″ are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 5. Acompound according to claim 4 wherein X and Y taken together with thecarbon atom to which they are attached are selected from the groupconsisting of: C═O, C═NR₃, C═N—O—R₆, C═N—C(O)R₃ andC═N—O—C(R₁₆)(R₁₇)—O—R₁₈, wherein R₃, R₆, R₁₆, R₁₇ and R₁₈ are as definedin claim
 1. 6. A compound according to claim 1 represented by theformula:

wherein A, B, X, Y, R₁₀ and R_(x) are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 7. Acompound according to claim 6 wherein X and Y taken together with thecarbon atom to which they are attached are selected from the groupconsisting of: C═O, C═NR₃, C═N—O—R₆, C═N—C(O)R₃ andC═N—O—C(R₁₆)(R₁₇)—O—R₁₈, wherein R₃, R₆, R₁₀, R₁₆, R₁₇ and R₁₈ are asdefined in claim
 1. 8. A compound according to claim 1 represented bythe formula:

wherein A, B, X, Y, R_(x) and R₄ are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof
 9. A compoundaccording to claim 8 wherein X and Y taken together with the carbon atomto which they are attached are selected from the group consisting of:C═O, C═NR₃, C═N—O—R₆, C═N—C(O)R₃ and C═N—O—C(R₁₆)(R₁₇)—O—R₁₈, whereinR₃, R₆, R₁₆, R₁₇ and R₁₈ are as defined in claim
 1. 10. A compoundaccording to claim 1 represented by the formula:

wherein A, B, X, Y, R₁₀ and R_(x) are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 11. Acompound according to claim 1 represented by the formula:

wherein A, B, X, Y, R_(x) and R₄ are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 12. Acompound according to claim 1 represented by the formula:

wherein A, B, X, Y, R₁₀ and R_(x) are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 13. Acompound according to claim 1 represented by the formula:

wherein Q, X, Y, R_(x) and R₄″ are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 14. Acompound according to claim 1 represented by the formula:

wherein Q, X, Y, R₁₀ and R_(x) are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 15. Acompound according to claim 1 represented by the formula:

wherein E, G, X, Y, R_(x) and R₄″ are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 16. Acompound according to claim 1 represented by the formula:

wherein E, G, X, Y, R₁₀ and R_(x) are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 17. Acompound according to claim 1 represented by the formula:

wherein X, Y, R₄, R₅, R_(x) and R₄ are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 18. Acompound according to claim 1 represented by the formula:

wherein X, Y, R₄, R₅, R₁₀ and R_(x) are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 19. Acompound according to claim 1 represented by the formula:

wherein X, Y, R₄, R₅, R_(x) and R₄″ are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 20. Acompound according to claim 1 represented by the formula:

wherein X, Y, R₄, R₅, R₁₀ and R_(x) are as defined in claim 1, or apharmaceutically acceptable salt, ester or prodrug thereof.
 21. Acompound according to claim 1 selected from the group consisting of:Compound of Formula (II): A=B=H; X and Y taken together with the carbonatom they are attached to=C═N—OH; R_(x)=H and R₄″=C(O)C₆H₅; Compound ofFormula (IV): A=3-quinolyl; B=H; X and Y taken together with the carbonatom they are attached to=C═N—OH; R_(x)=H and R₄″=C(O)CH₃; Compound ofFormula (II): A=C(O)OCH₃; B=H; X and Y taken together with the carbonatom they are attached to=C═N—OH; R_(x)=H and R₄″=C(O)C₆H₅; Compound ofFormula (II): A=B=H; X and Y taken together with the carbon atom theyare attached to=C═N—C(O)CH₃; R_(x)=H and R₄″=C(O)C₆H₅; Compound ofFormula (VIII): Q=—C(C₆H₅)═N—O—; X and Y taken together with the carbonatom they are attached to=C═N—C(O)CH₃; R_(x)=H and R₄″=C(O)C₆H₅;Compound of Formula (VIII): Q=—O—C(O)—O—; X and Y taken together withthe carbon atom they are attached to=C═N—C(O)CH₃; R_(x)=H andR₄″=C(O)C₆H₅; Compound of Formula (VIII): Q=—O—; X and Y taken togetherwith the carbon atom they are attached to=C═N—C(O)CH₃; R_(x)=H andR₄″=C(O)C₆H₅; Compound of Formula (VIII): Q=—O—; X and Y taken togetherwith the carbon atom they are attached to=C═N—C(O)CH₃; R_(x)=H andR₄″=H; Compound of Formula (II): A=B=H; X and Y taken together with thecarbon atom they are attached to=C═NC(O)CH₂OCH₃; R_(x)=H andR₄″=C(O)C₆H₅; Compound of Formula (II): A=B=H; X and Y taken togetherwith the carbon atom they are attached to=C═N—C(O)—CH₂OCH₃; R_(x)=H andR₄″=H; Compound of Formula (IV): A=3-quinolyl; B=H; X and Y takentogether with the carbon atom they are attached to=C═N—C(O)CH₃; R_(x)=Hand R₄″=C(O)C₆H₅; Compound of Formula (IV): A=3-quinolyl; B=H; X and Ytaken together with the carbon atom they are attached to=C═N—C(O)CH₃;R_(x)=H and R₄″=H; Compound of Formula (II): A=C(CH═CH—C₆H₅); B=H; X andY taken together with the carbon atom they are attached to=C═N—C(O)CH₃;R_(x)=H and R₄″=C(O)C₆H₅; Compound of Formula (II): A=C(CH═CH—C₆H₅);B=H; X and Y taken together with the carbon atom they are attachedto=C═NC(O)CH₃; R_(x)=H and R₄″=H; Compound of Formula (II):A=C(CH═CH—C₆H₅); B=H; X and Y taken together with the carbon atom theyare attached to=C═N—C(O)CH₃; R_(x)=H and R₄″C(O)C₆H₅; Compound ofFormula (II): A=C(CH═CH—C₆H₅); B=H; X and Y taken together with thecarbon atom they are attached to=C═NC(O)CH₃; R_(x)=H and R₄″=H; Compoundof Formula (II): A=H; B=H; X and Y taken together with the carbon atomthey are attached to=C═N—Ac; R_(x)=H and R₄″=H; Compound of Formula(II): A=C(O)—OH; B=H; X and Y taken together with the carbon atom theyare attached to=C═N—OH; R_(x)=H and R₄″=H; and Compound of Compound ofFormula (II): A=B=H, X and Y taken together with the carbon atom theyare attached to=C═O, R_(x)=H and R₄″=C(O)CH₃.
 22. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt, ester or prodrugthereof, in combination with a pharmaceutically acceptable carrier. 23.A method for controlling a bacterial infection in an animal comprisingadministering to an animal a therapeutically effective amount of apharmaceutical composition according to claim
 22. 24. A process forpreparing a compound of formula:

wherein A, B, and RX are as defined in claim 1, V taken together withthe carbon atom it is attached to is selected from the group consistingof: C═O, C═NR₃, C═N—O—R₆, C═N—C(O)R₃ and C═N—O—C(R₁₆)(R₁₇)—O—R₁₈, whereR₃, R₆, R₁₆, R₁₇ and R₁₈ are as defined in claim 1, and R₄″ is a hydroxyprotecting group; comprising the step of reacting a compound of theformula:

 wherein R₄″, RX and V are as defined previously, with an alkylatingagent of the formula:

 wherein R₁₉ is C₁-C₆ alkyl and A and B are as defined in claim 1, in anaprotic solvent in the presence of a palladium catalyst at a temperaturebetween room temperature and 80° C. to produce the claimed compound. 25.A process for preparing a compound of formula:

 wherein R₄″ is a hydroxy protecting group and A, B and R_(x) are asdefined in claim 1, the process comprising the steps: (a) hydrolyzing acompound of formula:

 wherein R₄″ is a hydroxy protecting group and A, B, R₆ and R_(x) are asdefined in claim 1,  in a protic solvent optionally with aqueous acid orbase to obtain the compound of formula:

 wherein R_(4.)″ A, B and R_(x) are as defined previously; and (b)reducing the product of step (a) with a reducing agent to obtain theclaimed compound.
 26. A process for preparing a compound of formula:

wherein A, B, R₃, R_(x) and R₄″ are as defined in claim 1; the processcomprising the step of acylating a compound of formula:

wherein A, B R_(x) and R₄ are as previously defined, with R₃C(O)T or(R₃C(O))₂O, where R₃ is as defined in claim 1 and T is a hydroxy groupor halogen, under basic conditions using an acylating agent in anaprotic solvent, optionally using an activation agent.
 27. A process forpreparing a compound of formula:

wherein R₄″ is a hydroxy protecting group, and A, B and R_(x) are asdefined in claim 1; the process comprising the steps: (a) reacting acompound of the formula:

 wherein R₄″ and V are as defined in claim 1 and R_(x) is as previouslydefined, with an alkylating agent of the formula:

 wherein R₁₉ is C₁-C₆ alkyl and A and B are as previously defined, in anaprotic solvent in the presence of a palladium catalyst at a temperaturebetween room temperature and 80° C. to produce the compound of formula:

 wherein R₆ is as defined in claim 1, R^(P) ₁ is H or R^(P) ₁ whereR^(P) is as defined in claim 1, and R_(4,)″ A, B and R_(x), are asdefined previously; (b) reacting the compound from step (a) with aprotic solvent optionally with aqueous base followed by reduction with areducing agent to produce a compound of formula:

 wherein R_(4,)″ A, B, R^(P) ₁ and R_(x) are as previously defined; (c)removing the R^(P) ₁ protecting group from the compound of step (b) andacylating the resulting hydroxy group with di-tert-butoxycarbonate toproduce compound of formula:

 wherein Boc is a tert-butoxycarbonyl group and wherein R_(4,)″ A, B andR_(x) are as previously defined; and (d) reacting the compound from step(b) with a palladium catalyst and a phosphorous ligand to obtain theclaimed compound.